Imidazo[1,5-a]pyrazine derivatives as PI3Kdelta inhibitors

ABSTRACT

Disclosed is a compound of Formula (I), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and pharmaceutical compositions comprising thereof. Also disclosed is a method of treating PI3Kδ related disorders or diseases by using the compound disclosed herein.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a U.S. National Stage Application under 35 U.S.C. §371 of International Application No. PCT/CN2018/104559, filed on Sep. 7,2018, which claims priority to, and the benefit of InternationalApplication Nos. PCT/CN2017/101058 filed on Sep. 8, 2017,PCT/CN2017/119373 filed on Dec. 28, 2017, and PCT/CN2018/086555 filed onMay 11, 2018, the disclosures of which are hereby incorporated byreference in their entireties for all purposes.

FIELD OF THE INVENTION

Disclose herein is an imidazo[1,5-a]pyrazine derivative, or astereoisomer thereof, or a pharmaceutically acceptable salt thereof, anda pharmaceutical composition comprising thereof. Also disclosed hereinis a method of treating PI3K-related disorders (in particularPI3Kδ-related disorders) using the imidazo[1,5-a]pyrazine derivativedisclosed herein, or a stereoisomer thereof, or a pharmaceuticallyacceptable salt thereof. Also disclosed herein is theimidazo[1,5-a]pyrazine derivative, or a stereoisomer thereof, or apharmaceutically acceptable salt thereof for use in the treatment ofPI3K-related disorders (in particular PI3Kδ-related disorders).

BACKGROUND OF THE INVENTION

Phosphatidylinositol-4,5-bisphosphate 3-kinases (PI3Ks) are a family ofenzymes involved in various of primary cellular functions, includingcell growth, proliferation, differentiation, motility, survival,metabolism and intracellular trafficking [Vanhaesebroeck, B., L.Stephens, and P. Hawkins, PI3K the path to discovery and understanding.Nat Rev Mol Cell Biol, 2012. 13(3): p. 195-203.]. They are kinasescapable of phosphorylating phosphatidylinositol [Whitman, M., et al.,Type I phosphatidylinositol kinase makes a novel inositol phospholipid,phosphatidylinositol-3-phosphate. Nature, 1988. 332(6165): p. 644-6.;Auger, K. R., et al., PDGF-dependent tyrosine phosphorylation stimulatesproduction of novel polyphosphoinositides in intact cells. Cell, 1989.57(1): p. 167-75]. Phosphorylated phosphatidylinositols, which arecalled phosphoinositide, play important roles in signaling transductionand membrane trafficking [Martin, T. F., Phosphoinositide lipids assignaling molecules: common themes for signal transduction, cytoskeletalregulation, and membrane trafficking. Anna Rev Cell Dev Biol., 1998. 14:p. 231-64].

PI3K family is divided into three classes II, and III) based onstructure, regulation and substrate specificity [Vanhaesebroeck, B., etal., The emerging mechanisms of isoform- Specific PI3K signalling. NatRev Mol Cell Biol, 2010. 11(5): p. 329-41.]. Class I PI3Ks are furtherdivided based on sequence similarity into class IA and class IB. Theclass IA PI3Ks comprise three closely related kinases, PI3Kα, PI3Kβ, andPI3Kδ, which exist as heterodimers composed of a catalytic subunit(p110α, p110β, or p110δ) and a regulatory subunit (p85) [Yu, J., et al.,Regulation of the p85/p110 phosphatidylinositol 3′-kinase: stabilizationand inhibition of the p110alpha catalytic subunit by the p85 regulatorysubunit. Mol Cell Biol, 1998. 18(3): p. 1379-87; Carpenter, C. L., etal., Phosphoinositide 3-kinase is activated by phosphopeptides that bindto the SH2 domains of the 85-kDa subunit. J Biol Chem, 1993. 268(13): p.9478-83; Zhang, X., et al., Structure of lipid kinase p110beta/p85betaelucidates an unusual SH2-domain-mediated inhibitory mechanism. MolCell, 2011. 41(5): p. 567-78; Burke, J. E., et al., Dynamics of thephosphoinositide 3-kinase p110delta interaction with p85alpha andmembranes reveals aspects of regulation distinct from p110alpha.Structure, 2011. 19(8): p. 1127-37.]. The class IB PI3K includes onlyPI3Kγ, which is composed of a p110γ [Stoyanov, B., et al., Cloning andcharacterization of a G protein-activated human phosphoinositide-3kinase. Science, 1995. 269(5224): p. 690-3.] catalytic subunit that canassociate with a p101 [Stephens, L. R., et al., The G beta gammasensitivity of a PI3K is dependent upon a tightly associated adaptor,p101. Cell, 1997. 89(1): p. 105-14; Brock, C., et al., Roles of G betagamma in membrane recruitment and activation of p110 gamma/p101phosphoinositide 3-kinase gamma. J Cell Biol, 2003, 160(1): p. 89-99,]or p84[Suire, S., et al., p84, a new Gbetagamma-activated regulatorysubunit of the type IB phosphoinositide 3-kinase p110gamma. Curr Biol.,2005. 15(6): p. 566-70.] regulatory subunit. PI3Kα and PI3Kδ respond tosignaling generally through receptor tyrosine kinases (RTKs) [Inukai,K., et al., Five isoforms of the phosphatidylinositol 3-kinaseregulatory subunit exhibit different associations with receptor tyrosinekinases and their tyrosine phosphorylations. FEBS Lett, 2001. 490(1-2):p. 32-8.], while PI3Kγ signals through G-protein-coupled receptors(GPCRs) [Stoyanov, B., et al., Cloning and characterization of a Gprotein-activated human phosphoinositide-3 kinase. Science, 1995.269(5224): p. 690-3; Maier, U., A. Babich, and B. Nurnberg, Roles ofnon-catalytic subunits in gbetagamma-induced activation of class Iphosphoinositide 3-kinase isoforms beta and gamma. J Biol Chem, 1999.274(41): p. 29311-7.] and PI3Kβ signals through both [Kurosu, H., etal., Heterodimeric phosphoinositide 3-kinase consisting of p85 andp110beta is synergistically activated by the betagamma subunits of Gproteins and phosphotyrosyl peptide. J Biol Chem, 1997. 272(39): p.24252-6]. Expression of the PI3Kα and PI3Kβ isoforms is ubiquitous,while the expression pattern of PI3Kδ and PI3Kγ seems more restricted,with both isoforms found primarily in leukocytes [Kok, K., B. Geering,and B. Vanhaesbroeck, Regulation of phosphoinositide 3-kinase expressionin health and disease. Trends Biochem Sci, 2009. 34(3): p. 115-27].

The relatively restricted expression pattern of PI3Kδ, in addition todata accumulated from studies in mice, where PI3Kδ was eithergenetically inactivated or hyper-activated or pharmacologicallyinactivated, suggests that this isoform plays a major role in theadaptive immune systems[Lucas, C. L., et al., PI3Kdelta and primaryimmunodeficiencies. Nat Rev Immunol, 2016.]. In mice, the loss offunction of PI3Kδ in B cells impairs the T cell-independent antibodyresponse but has no effect on class-switch recombination (CSR) andsomatic hypermutation (SHM) [Rolf, J., et al., Phosphoinositide 3-kinaseactivity in T cells regulates the magnitude of the germinal centerreaction. J Immunol, 2010. 185(7): p. 4042-52.], both of which areessential for antibody maturation and diversity [Stavnezer, J., J. E.Guikema, and C. E. Schrader, Mechanism and regulation of class switchrecombination. Annu Rev Immunol., 2008. 26: p. 261-92; Li, Z., et al.,The generation of antibody diversity through somatic hypermutation andclass switch recombination. Genes Dev, 2004. 18(1): p. 1-11.]; while thehyperactivation of PI3Kδ in mature B cells interferes with CSR and SHMand inhibits the proliferation of antigen-specific B cell populations[Janas, M. L., et al., The effect of deleting p110delta on the phenotypeand, function of PTEN-deficient B cells. J Immunol, 2008. 180(2): p.739-46; Omori, S, A., et al., Regulation of class-switch recombinationand plasma cell differentiation by phosphatidylinositol 3-kinasesignaling. Immunity, 2006, 25(4): p. 545-57; Sander, S., et al., PI3Kinase and FOXO1 Transcription Factor Activity Differentially Control BCells in the Germinal Center Light and Dark Zones. Immunity, 2015.43(6): p. 1075-86.]. Besides, PI3Kδ is also a key signaling transductioncomponent for malignant B cells, which makes it an attractive drugtarget for B cell malignancies [Wei, M., et al., Targeting PI3Kdelta:emerging therapy for chronic lymphocytic leukemia and beyond. Med ResRev, 2015. 35(4): p. 720-52.].

Meanwhile, PI3Kδ is required for the differentiation of nave T celltowards T helper cells, including T_(FH) (follicular helper) [Rolf, J.,et al., Phosphoinositide 3-kinase activity in T cells regulates themagnitude of the germinal center reaction. J Immunol, 2010. 185(7): p.4042-52.], T_(H)1, T_(H)2 and T_(H)17[Okkenhaug, K., et al., Thep110delta isoform of phosphoinositide 3-kinase controls clonal expansionand differentiation of Th cells. J Immunol, 2006. 177(8): p. 5122-8;Soond, D. R., et al., PI3K p110delta regulates T-cell cytokineproduction during primary and secondary immune responses in mice andhumans. Blood, 2010. 115(11): p. 2203-13; Kurebayashi, Y., et al.,PI3K-Akt-mTORC1-S6K1/2 axis controls Th17 differentiation by regulatingGfi1 expression and nuclear translocation of RORgamma, Cell Rep, 2012.1(4): p. 360-73.]. The interference on T_(FH) development leads tosevere attenuation of T cell-dependent CSR and SHM in B cells [Rolf, J.,et al., Phosphoinositide 3-kinase activity in T cells regulates themagnitude of the germinal center reaction. J Immunol, 2010. 185(7): p.4042-52.], whereas the reduction on T_(H)2 and T_(H)17 cells induced byPI3Kδ deficiency could provide protections on mice with asthma [Nashed,B. F., et al., Role of the phosphoinositide 3-kinase p110delta ingeneration of type 2 cytokine responses and allergic airwayinflammation. Eur J Immunol, 2007. 37(2): p. 416-24.] or multiplesclerosis [Haylock-Jacobs, S., et al., PI3Kdelta drives the pathogenesisof experimental autoimmune encephalomyelitis by inhibiting effector Tcell apoptosis and promoting Th17 differentiation. J Autoimmun, 2011.36(3-4): p. 278-87.] respectively. PI3Kδ is also essential for thehomeostasis and function of Foxp³⁺ T regulatory cells (T_(reg)) [Patton,et al., Cutting edge: the phosphoinositide 3-kinase p110 delta iscritical for the function of CD4+CD25+Foxp3+ regulatory T cells. JImmunol, 2006. 177(10): p. 6598-602.]. PI3Kδ deficient mice developcolitis [Patton, D. T., et al., Cutting edge: the phosphoinositide3-kinase p110 delta is critical for the function of CD4+CD25+Foxp3+regulatory T cells. J Immunol, 2006. 177(10): p. 6598-602.] due to thereduced T_(reg) functions but have increased immune response againsttumors [Ali, K., et al., Inactivation of PI(3)K p110delta breaksregulatory T-cell-mediated immune tolerance to cancer. Nature, 2014.510(7505): p. 407-11.]. PI3Kδ also contributes to, but is not necessaryfor the reprogramming of CD8+ T cells to fully activated effector cells[Pearce, V. Q., et al., PI3Kdelta Regulates the Magnitude of CD8+ T CellResponses alter Challenge with Listeria monocytogenes. J Immunol, 2015.195(7): p. 3206-17; Gracias, D. T., et al., Phosphatidylinositol3-Kinase p110delta Isoform Regulates CD8+ T Cell Responses during AcuteViral and Intracellular Bacterial Infections. J Immunol, 2016. 196(3):p. 1186-98.]. In contrast, the generation of memory CD8+ T cellsrequires the suppression of PI3Kδ signaling [Pearce, V. Q., et al.,PI3Kdelta Regulates the Magnitude of CD8+ T Cell Responses afterChallenge with Listeria monocytogenes. J Immunol, 2015. 195(7): p.3206-17.].

PI3Kδ mutations, both gain of function (GOF) and loss of function (LOF),can induce primary immunodeficiency in human [Lucas, C. L., et al.,PI3Kdelta and primary immunodeficiencies. Nat Rev Immunol, 2016].Patients lacking of PI3Kδ function presented with recurrent infectionsand severe B cell lymphopenia [Conley, M. E., et al., Agammaglobulinemiaand absent B lineage cells in a patient lacking the p85alpha subunit ofPI3K. J Exp Med, 2012. 209(3): p. 463-70; Conley, M. E., et al.,Agammaglobulinemia and absent B lineage cells in a patient lacking thep85alpha subunit of PI3K. J Exp Med, 2012. 209(3): p. 463-70.], whileGOP mutations in PI3Kδ genes can cause a syndrome of combinedimmune-deficiency, which is referred to as activated PI3Kδ syndrome(APDS) [Angulo, I., et al., Phosphoinositide 3-kinase delta genemutation predisposes to respiratory infection and airway damage.Science, 2013. 342(6160): p. 866-71; Lucas, C. L., et al.,Dominant-activating germline mutations in the gene encoding the PI(3)Kcatalytic subunit p110delta result in T cell senescence and humanimmunodeficiency. Nat Immunol, 2014. 15(1): p. 88-97; Deau, M. C., etal., A human immunodeficiency caused by mutations in the PIK3R1 gene. JClin Invest, 2015. 125(4): p. 1764-5; Lucas, C. L., et al., Heterozygoussplice mutation in PIK3R1 causes human immunodeficiency withlymphoproliferation due to dominant activation of PI3K. J Exp Med, 2014.211(13): p. 2537-47.]. Patients with APDS were characterized withsenescent T cells, lymphadenopathy and frequent infections [Elgizouli,M., et al., Activating PI3Kdelta mutations in a cohort of 669 patientswith primary immunodeficiency. Clin Exp Immunol, 2016. 183(2): p. 221-9;Elkaim, E., et al., Clinical and immunologic phenotype associated withactivated phosphoinositide 3-kinase delta syndrome 2: A cohort study. JAllergy Clin Immunol, 2016. 138(1): p. 10-218 e9.; Coulter, T. I., etal., Clinical spectrum and features of activated phosphoinositide3-kinase delta syndrome: A large patient cohort study. J Allergy ClinImmunol, 2016.].

Because of the specific and critical functions of PI3Kδ in adaptiveimmune responses, the inhibitors of PI3Kδ are being developed for thetreatment of autoimmune (such as multiple sclerosis, systemic lupuserythematosus, rheumatoid arthritis and psoriasis) and inflammatorydisorders (such as asthma and chronic obstructive pulmonary disease),hematological and solid tumors as well as APDS [Lucas, C. L et al.,PI3Kdelta and primary immunodeficiencies. Nat Rev Immunol., 2016; Stark,A. K., et al., PI3K inhibitors in inflammation, autoimmunity and cancer.Curr Opin Pharmacol, 2015. 23: p. 82-91.]. Idelalisib is the first PI3Kδinhibitor approved in 2014 for the treatment of B cell malignancies[Yang, Q., et al., Idelalisib: First-in-Class PI3K Delta Inhibitor forthe Treatment of Chronic Lymphocytic Leukemia, Small LymphocyticLeukemia, and Follicular Lymphoma. Clin Cancer Res, 2015. 21(7): p.1537-42.], In addition to idelalisib, at least 9 δ-specific and 5 δγ, δβor δα-dual inhibitors are under clinical development [Wei., M., et al.,Targeting PI3Kdelta: emerging therapy, for chronic lymphocytic leukemiaand beyond. Med Res Rev, 2015. 35(4): p. 720-52.]. Among them, a δγ-dualinhibitor duvelisib (NCT02004522) and a δ-specific inhibitor TGR-1202(NCT0261311) are being evaluated in phase III clinical trials.

Recently, both idelalisib and duvelisib were noted with the risk ofincreasing infections in lung [Okkenhaug, K., M. Graupera, and B.Vanhaesebroeck, Targeting PI3K in Cancer: Impact on Tumor Cells, TheirProtective Stroma, Angiogenesis, and Immunotherapy. Cancer Discov, 2016.6(10): p. 1090-1105.], which was inferred to be associated with theirrelatively low selectivity to PI3Kγ [Ruckle, T., M. K. Schwarz, and C.Rommel, PI3Kgamma inhibition: towards an ‘aspirin of the 21st century’?Nat Rev Drug Discov, 2006. 5(11): p. 903-18.]. PI3Kγ is important forimmune cell chemotaxis [Hawkins, P. T. and L. R. Stephens, PI3Ksignalling in inflammation. Biochim Biophys Acta, 2015. 1851(6): p.882-97,] and plays major roles in innate immune system [T., M. K.Schwarz, and C. Rommel, PI3Kgamma towards an ‘aspirin of the 21stcentury’? Nat Rev Drug Discov, 2006. 5(11): p. 903-18.]. PI3Kγ knock-outmice displayed increased susceptibility to pneumococcal infection [Maus,U. A., et al., Importance of phosphoinositide 3-kinase gamma in the hostdefense against pneumococcal infection. Am J Respir Crit Care Med, 2007.175(9): p. 958-66.]. It also works in concert with PI3Kδ in multipleimmune surveillance processes, including neutrophil recruitment [Liu,L., et al., Leukocyte PI3Kgamma and PI3Kdelta have temporally distinctroles for leukocyte recruitment in vivo. Blood, 2007. 110(4): p.1191-8.] and T cell development [Webb, L. M., et al., Cutting edge: Tcell development requires the combined activities of the p110gamma andp110delta catalytic isoforms of phosphatidylinositol 3-kinase. JImmunol, 2005. 175(5): p, 2783-7.]. The simultaneous geneticinactivation of PI3Kδ and PI3Kγ in mice leads to more severe impairmentof thymocyte development and multiple organ inflammation [Ji, H., etal., Inactivation of PI3Kgamma and PI3Kdelta distorts T-cell developmentand causes multiple organ inflammation. Blood, 2007. 110(8): p. 2940-7.]than in the mice with the deficiency of each isoform alone [Swat, W., etal., Essential role of PI3Kdelta and PI3Kgamma in thymocyte survival.Blood, 2006. 107(6): p. 2415-22.].

Therefore, there is a need of PI3Kδ inhibitors with higher selectivityagainst PI3Kα, β and γ as the selective PI3Kδ inhibitors are expected tohave improved safety profile and would provide new therapeutic optionsfor APDS, autoimmune and inflammatory disorders as well as cancer, e.g.,glioblastoma.

SUMMARY OF THE INVENTION

The above need is met by the compounds, compositions and methodsdisclosed herein.

Disclosed herein is a compound of Formula (I),

or a stereoisomer thereof, or a pharmaceutically acceptable saltthereof, wherein:

R₁ is —NR_(a)R_(b), wherein R_(a) and R_(b) are each independentlyhydrogen or C₁₋₆alkyl;

R₂ is hydrogen, F, Cl, Br, —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl,cycloalkyl, heterocyclyl, aryl, heteroaryl, —CN, —NO₂, —OR₁₂, —SO₂R₁₂,—COR₁₂, —CO₂R₁₂, —CONR₁₂R₁₃; C(═NR₁₂)NR₁₃R₁₄, —NR₁₂R₁₃, —NR₁₂COR₁₃,—NR₁₂CONR₁₃R₁₄, —NR₁₂CO₂R₁₃, —NR₁₂SONR₁₃R₁₄; —N₁₂SO₂NR₁₃R₁₄, or—NR₁₂SO₂R₁₃; wherein said —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl,cycloalkyl, heterocyclyl, aryl or heteroaryl are each independentlyoptionally substituted with at least one substituent Rita;

R₃ and R₄, which may be the same or different, are each independentlyhydrogen, —C₁₋₆alkyl cycloalkyl, heterocyclyl, aryl, or heteroaryl;

R₅ and R₆, which may be the same or different, are each independentlyhydrogen, halogen, —C₁₋₆alkenyl, —C₂₋₆alkynyl, cycloalkyl, heterocyclyl,aryl, heteroaryl, —CN, —NO₂, —OR₁₂, —SO₂R₁₂, —COR₁₂, —CO₂R₁₂,—CONR₁₂R₁₃, —C(═NR₁₂)NR₁₃R₁₄, —NR₁₂R₁₃, —NR₁₂COR₁₃, —NR₁₂CONR₁₃R₁₄,—NR₁₂CO₂R₁₃, —NR₁₂SONR₁₃R₁₄, —NR₁₂SO₂NR₁₃R₁₄, or —NR₁₂SO₂R₁₃; whereinsaid —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, cycloalkyl, heterocyclyl,aryl or heteroaryl are each independently optionally substituted with atleast one substituent R_(11b);

R₇; R₈ and R₁₀, which may be the same or different, are eachindependently hydrogen, halogen, —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl,cycloalkyl, heterocyclyl, aryl, heteroaryl, —CN, —NO₂, —OR₁₂, —SO₂R₁₂;—COR₁₂, —CO₂R₁₂, —CONR₁₂R₁₃, —C(═NR₁₂)NR₁₃R₁₄, —NR₁₂R₁₃, —NR₁₂COR₁₃,—NR₁₂CONR₁₃R₁₄, —NR₁₂CO₂R₁₃, —NR₁₂SONR₁₃R₁₄, —NR₁₂SO₂NR₁₃R₁₄, or—NR₁₂SO₂R₁₃; wherein said —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl,cycloalkyl, heterocyclyl, aryl or heteroaryl are each independentlyoptionally substituted with at least one substituent R_(11c);

R₉ is —CN, —NO₂, —OR₁₂, —SO₂R₁₂, —SO₂NR₁₂R₁₃, —COR₁₂, —CO₂R₁₂,—CONR₁₂R₁₃, —C(═NR₁₂)NR₁₃R₁₄, —NR₁₂COR₁₃, —NR₁₂CONR₁₃R₁₄, —NR₁₂CO₂R₁₃,—NR₁₂SONR₁₃R₁₄, —NR₁₂SO₂NR₁₃R₁₄, or —NR₁₂SO₂R₁₃;

R₁₁, R_(11b), and R_(11c), which may be the same or different, are eachindependently hydrogen, halogen, —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl,haloC₁₋₆alkyl, haloC₂₋₆alkenyl, haloC₂₋₆alkynyl, cycloalkyl,heterocyclyl, aryl, heteroaryl, —CN, —NO₂, oxo, —OR₁₂, —SO₂R₁₂, —COR₁₂,—CO₂R₁₂, —CONR₁₂R₁₃, —C(═NR₁₂)NR₁₃R₁₄, —NR₁₂COR₁₃, —NR₁₂CONR₁₃R₁₄,—NR₁₂CO₂R₁₃, —NR₁₂SONR₁₃R₁₄, —NR₁₂SO₂NR₁₃R₁₄, or —NR₁₂SO₂R₁₃; and

R₁₂, R₁₃, and R₁₄, which may be the same or different, are eachindependently hydrogen, —C₁₋₆alkyl, —C₂₋₆alkenyl; —C₂₋₆alkynyl,cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein said C₁₋₆alkyl,—C₂₋₆alkenyl, —C₂₋₆alkynyl, cycloalkyl, heterocyclyl, aryl, orheteroaryl are each independently optionally substituted with at leastone substituent R₁₅;

Alternatively, (R₁₂ and R₁₃), or (R₁₃ and R₁₄), or (R₁₂ and R₁₄),together with the atom(s) to which they are attached, form a 3- to12-membered saturated, partially or fully unsaturated ring comprising 0,1 or 2 additional heteroatoms independently selected from —NH, —O—, —S—,—SO— or —SO₂—, and said ring is optionally substituted with at least onesubstituent R₁₅;

R₁₅, at each of its occurrences, is independently hydrogen, halogen,—C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, cycloalkyl, heterocyclyl, aryl,heteroaryl, —CN, —NO₂, oxo, —OR₁₆, —SO₂R₁₆, —COR₁₆, —CO₂R₁₆, —CONR₁₆R₁₇,—C(═NR₁₆)NR₁₇R₁₈, —NR₁₆R₁₇, —C₁₋₆alkyl-NR₁₆R₁₇, —NR₁₆COR₁₇,—NR₁₆CONR₁₇R₁₈, —NR₁₆CO₂R₁₇, —NR₁₆SONR₁₇R₁₈, —NR₁₆SO₂NR₁₇R₁₈, or—NR₁₆SO₂R₁₇, wherein said C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl,cycloalkyl, heterocyclyl, aryl, or heteroaryl are each independentlyoptionally substituted with halogen, R₁₉, —OR₁₉, —COR₁₉, —SO₂R₁₉, or—CO₂R₁₉;

-   -   wherein each of R₁₆, R₁₇, or R₁₈ is independently hydrogen,        —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, haloC₂₋₆alkenyl,        haloC₂₋₆alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl;        or    -   (R₁₆ and R₁₇), or (R₁₆ and R₁₈), or (R₁₇ and R₁₈), together with        the atom(s) to which they are attached, form a 3- to 12-membered        saturated, partially or fully unsaturated ring comprising 0, 1        or 2 additional heteroatoms independently selected from —NH,        —O—, —S—, —SO— or —SO₂—, and said ring is optionally substituted        with at least one substituent R₁₉; and    -   wherein R₁₉ is independently hydrogen, —C₁₋₆alkyl, —C₂₋₆alkenyl,        —C₂₋₆alkynyl, haloC₂₋₆alkenyl, haloC₂₋₆alkynyl, cycloalkyl,        heterocyclyl, aryl, or heteroaryl, wherein said cycloalkyl,        heterocyclyl, aryl, or heteroaryl are each optionally        substituted with halogen, —C₁₋₆alkyl, —C₂₋₆alkenyl,        —C₂₋₆alkynyl, haloC₂₋₆alkenyl, or haloC₂₋₆alkynyl; and wherein        said —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, haloC₁₋₆alkyl,        haloC₂₋₆alkenyl, or haloC₂₋₆alkynyl are each optionally        substituted with cycloalkyl, heterocyclyl, aryl, or heteroaryl.

Disclosed herein also is a pharmaceutical composition, comprising atherapeutically effective amount of a compound of Formula (I), or astereoisomer thereof or a pharmaceutically acceptable salt thereofdisclosed herein, and a pharmaceutically acceptable excipient.

The compound of Formula (I) disclosed herein is useful as a PI3Kinhibitor, in particular, a PI3Kδ inhibitor. The compound of Formula (I)disclosed herein is thus useful in treating or preventing idiopathicthrombocytopenic purpura (ITP), autoimmune hemolytic anemia, vasculitis,systemic lupus erythematosus, lupus nephritis, pemphigus, membranousnephropathy, chronic lymphocytic leukemia (CLL), Non-Hodgkin lymphoma(NHL), hairy cell leukemia, Mantle cell lymphoma, small lymphocyticlymphoma, follicular lymphoma, lymphoplasmacytic lymphoma, extranodalmarginal zone lymphoma, activated B-cell like (ABC) diffuse large B celllymphoma, or germinal center B cell (GCB) diffuse large B cell lymphomain a subject. Thus, compositions and methods for treating variousdisorders or diseases mentioned above using the compound of Formula (I)are disclosed herein, and use of the compound of Formula (I) inmanufacturing medicine for treating various disorders or diseasesmentioned above, are also disclosed herein.

DETAILED DESCRIPTION OF THE INVENTION

In the first aspect, disclosed herein is a compound of Formula (I),

or a stereoisomer thereof, or a pharmaceutically acceptable saltthereof,wherein:

R₁ is —NR_(a)R_(b), wherein R_(a) and R_(b) are each independentlyhydrogen or C₁₋₆alkyl;

R₂ is hydrogen, F, Cl, Br, —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl,cycloalkyl, heterocyclyl, aryl, heteroaryl, —CN, —NO₂, —OR₁₂, —SO₂R₁₂,—COR₁₂, —CO₂R₁₂, —CONR₁₂R₁₃, —C(═NR₁₂)NR₁₂R₁₄, —NR₁₂R₁₃, —NR₁₂COR₁₃,—NR₁₂CONR₁₃R₁₄, —NR₁₂CO₂R₁₃, —NR₁₂SONR₁₃R₁₄, —N₁₂SO₂NR₁₃R₁₄, or—NR₁₂SO₂R₁₃; wherein said —C₁₋₆alkyl, —C₂₋₆ alkenyl, —C₂₋₆alkynyl,cycloalkyl, heterocyclyl, aryl or heteroaryl are each independentlyoptionally substituted with at least one substituent R_(11a);

R₃ and R₄, which may be the same or different, are each independentlyhydrogen, —C₁₋₆cycloalkyl, heterocyclyl, aryl, or heteroaryl;

R₅ and R₆, which may be the same or different, are each independentlyhydrogen, halogen, —C₂₋₆alkenyl, cycloalkyl, heterocyclyl, aryl,heteroaryl, —CN, —NO₂, —OR₁₂, —SO₂R₁₂, —COR₁₂, —CO₂R₁₂, —CONR₁₂R₁₃,—C(═NR₁₂)NR₁₃R₁₄, —NR₁₂R₁₃, —NR₁₂COR₁₃, —NR₁₂CONR₁₂R₁₃, —NR₁₂CO₂R₁₃,—NR₁₂SONR₁₂R₁₃, —NR₁₂SO₂NR₁₃R₁₄, or —NR₁₂SO₂R₁₃; wherein said—C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, cycloalkyl, heterocyclyl, arylor heteroaryl are each independently optionally substituted with atleast one substituent R_(11b);

R₇, R₈ and R₁₀, which may be the same or different, are eachindependently hydrogen, halogen, —C₁₋₆ alkyl, —C₂₋₆alkynyl,—C₂₋₆alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, —CN, —NO₂,—OR₁₂, —SO₂R₁₂, —CO₂R₁₂, —CONR₁₂R₁₃, —C(═NR₁₂)NR₁₃R₁₄, —NR₁₂R₁₃,—NR₁₂COR₁₃, —NR₁₂CONR₁₃R₁₄, —NR₁₂CO₂R₁₃, —NR₁₂SONR₁₂R₁₃,—NR₁₂SO₂NR₁₃R₁₄, or —NR₁₂SO₂R₁₃; wherein said —C₁₋₆alkyl, —C₂₋₆alkenyl,—C₂₋₆alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl are eachindependently optionally substituted with at least one substituentR_(11c);

R₉ is —CN, —NO₂, —OR₁₂, —SO₂R₁₂, —SO₂NR₁₂R₁₃, —COR₁₂, —CO₂R₁₂,—CONR₁₂R₁₃, —C(═NR₁₂)NR₁₃R₁₄, —NR₁₂COR₁₃, —NR₁₂CONR₁₃R₁₄, —NR₁₂CO₂R₁₃,—NR₁₂SONR₁₃R₁₄, —NR₁₂SO₂NR₁₃R₁₄, or —NR₁₂SO₂R₁₃;

R_(11a), R_(11b), and R_(11c), which may be the same or different, areeach independently hydrogen, halogen, —C₁₋₆alkyl, —C₂₋₆alkenyl,—C₂₋₆alkynyl, haloC₁₋₆alkyl, haloC₂₋₆alkenyl, haloC₂₋₆alkynyl,cycloalkyl, heterocyclyl, aryl, heteroaryl, —CN, —NO₂, oxo, —OR₁₂,—SO₂R₁₂, —COR₁₂, —CO₂R₁₂, —CONR₁₂R₁₃, —C(═NR₁₂)NR₁₃R₁₄, —NR₁₂R₁₃,—NR₁₂COR₁₃, —NR₁₂CONR₁₃R₁₄, —NR₁₂CO₂R₁₃, —NR₁₂SONR₁₂R₁₃,—NR₁₂SO₂NR₁₃R₁₄, or —NR₁₂SO₂R₁₃; and

R₁₂, R₁₃, and R₁₄, which may be the same or different, are eachindependently hydrogen, —C₁₋₆alkyl, —C₂₋₆alkenyl, cycloalkyl,heterocyclyl, aryl, or heteroaryl, wherein said C₁₋₆alkyl, —C₂₋₆alkenyl,—C₂₋₆alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl are eachindependently optionally substituted with at least one substituent R₁₅;

Alternatively, (R₁₂ and R₁₃), or (R₁₃ and R₁₄), or (R₁₂ and R₁₄),together with the atom(s) to which they are attached, form a 3- to12-membered saturated, partially or fully unsaturated ring comprising 0,1 or 2 additional heteroatoms independently selected from —NH, —O—, —S—,—SO— or —SO₂—, and said ring is optionally substituted with at least onesubstituent R₁₅;

R₁₅, at each of its occurrences, is independently hydrogen, halogen,—C₁₋₆ alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, cycloalkyl, heterocyclyl, aryl,heteroaryl, —CN, —NO₂, oxo, —OR₁₆, —SO₂R₁₆, —COR₁₆, —CO₂R₁₆, —CONR₁₆R₁₇,—C(═NR₁₆)NR₁₇R₁₈, —NR₁₆R₁₇, —C₁₋₆alkyl-NR₁₆R₁₇, —NR₁₆COR₁₇,—NR₁₆CONR₁₇R₁₈, —NR₁₆CO₂R₁₇, —NR₁₆SONR₁₇R₁₈, —NR₁₆SO₂NR₁₇R₁₈, or—NR₁₆SO₂R₁₇, wherein said C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl,cycloalkyl, heterocyclyl, aryl, or heteroaryl are each independentlyoptionally substituted with halogen, R₁₉, —OR₁₉, —COR₁₉, —SO₂R₁₉, or—CO₂R₁₉;

-   -   wherein each of R₁₆, R₁₇, or R₁₈ is independently hydrogen,        —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, haloC₂₋₆ alkyl,        haloC₂₋₆alkenyl, haloC₂₋₆alkynyl, cycloalkyl, heterocyclyl,        aryl, or heteroaryl; or    -   (R₁₆ and R₁₇), or (R₁₆ and R₁₈), or (R₁₇ and R₁₈), together with        the atom(s) to which they are attached, form a 3- to 12-membered        saturated, partially or fully unsaturated ring comprising 0, 1        or 2 additional heteroatoms independently selected from —NH,        —O—, —S—, —SO— or —SO₂—, and said ring is optionally substituted        with at least one substituent R₁₉; and    -   wherein R₁₉ is independently hydrogen, —C₁₋₆alkyl, —C₂₋₆alkenyl,        —C₂₋₆alkynyl, haloC₁₋₆alkyl, haloC₂₋₆alkenyl, haloC₂₋₆alkynyl,        cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein said        cycloalkyl, heterocyclyl, aryl, or heteroaryl are each        optionally substituted with halogen, —C₁₋₆alkyl, —C₂₋₆ alkenyl,        —C₂₋₆alkynyl, haloC₂₋₆alkyl, haloC₂₋₆alkenyl, or haloC₂₋₆        alkynyl; and wherein said —C₁₋₆alkyl, —C₂₋₆alkenyl,        —C₂₋₆alkynyl, haloC₁₋₆alkyl, haloC₂₋₆alkenyl, or haloC₂₋₆alkynyl        are each optionally substituted with cycloalkyl, heterocyclyl,        aryl, or heteroaryl.

In an embodiment of the first aspect, R₁ is —NH₂.

In an embodiment of the first aspect, R₂ is independently hydrogen,halogen, —C₁₋₆alkyl, C₃₋₆cycloalkyl or C₆₋₁₀ aryl, and wherein—C₁₋₆alkyl, C₃₋₆ cycloalkyl and C₆₋₁₀ aryl are each independentlyoptionally substituted with at least one substituent R_(11a);preferably, R₂ is C₁₋₆alkyl; more preferably, R₂ is C₁₋₃alkyl; even morepreferably, R₂ is methyl.

In an embodiment of the first aspect, R₃ and R₁ are each independentlyhydrogen or —C₁₋₆alkyl. In another embodiment of the first aspect, R₃ ishydrogen, and R₄ is —C₁₋₆alkyl; preferably, R₃ is hydrogen, and R₄ is—C₁₋₃alkyl; more preferably, R₃ is hydrogen, and R₄ is methyl.

In an embodiment of the first aspect, R₅ and R₆, which may be the sameor different, are each independently hydrogen, halogen, —C₁₋₆alkyl,—C₂₋₆alkenyl, —C₂₋₆alkynyl, cycloalkyl, heterocyclyl, aryl, orheteroaryl, wherein said —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl,cycloalkyl, heterocyclyl, aryl or heteroaryl are each independentlyoptionally substituted with at least one substituent R_(11b), whereinR_(11b) is halogen. In a preferred embodiment, R₅ and R₆ are eachindependently hydrogen, halogen, or —C₁₋₆alkyl; in a further preferredembodiment, R₅ and R₆ are both hydrogen.

In an embodiment of the first aspect, R₇, R₈ and R₁₀, which may be thesame or different, are each independently hydrogen, halogen, —C₁₋₆alkyl,—C₂₋₆alkenyl, —C₂₋₆alkenyl, cycloalkyl, heterocyclyl, aryl, heteroaryl,or —OR₁₂; wherein said —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl,cycloalkyl heterocyclyl, acyl or heteroaryl are each independentlyoptionally substituted with at least one substituent R_(11c), whereinR_(11c) is halogen. In a preferred embodiment, R₇ and R₈ are eachindependently hydrogen, halogen or —C₁₋₆alkyl, and R₁₀ is —OR₁₂. In amore preferred embodiment, R₇ and R₈ are each independently halogen, andR₁₀ is C₁₋₆alkoxy. In an even more preferred embodiment, R₇ is Cl, R₈ isF, and R₁₀ is isopropoxy.

In an embodiment of the first aspect, R₉ is —CONR₁₂R₁₃, wherein R₁₂ andR₁₃ are as defined in Formula (1).

In a preferred embodiment, R₉ is —CONR₁₂R₁₃, wherein R₁₂ and R₁₃ areeach hydrogen or C₁₋₆alklyl optionally substituted with at least onesubstituent R₁₅. More preferably, R₁₂ and R₁₃ are each hydrogen ormethyl, ethyl, n-propyl or isopropyl, each optionally substituted withat least one substituent R₁₅. In this embodiment, R₁₅ is preferablyhydrogen, cycloalkyl, heterocyclyl, —OR₁₆, or —NR₁₆R₁₇, wherein R₁₆ andR₁₇ are as defined in Formula (I) and wherein said cycloalkyl, aryl, orheterocyclyl are each independently optionally substituted with halogen,R₁₉, —OR₁₉, —COR₁₉, —SO₂R₁₉, or —CO₂R₁₉, wherein R₁₉ is as defined inFormula (I).

In a preferred embodiment, R₉ is —CONR₁₂R₁₃, wherein R₁₂ and R₁₃ areeach hydrogen or C₁₋₆alklyl optionally substituted with one substituentR₁₅, which is heterocyclyl optionally substituted with halogen, R₁₉,—OR₁₉, —COR₁₉, —SO₂R₁₉, or —CO₂R₁₉, wherein R₁₉ is as defined in Formula(I). More preferably, R₁₂ is hydrogen and R₁₃ is C₁₋₆alklyl optionallysubstituted with one substituent R₁₅, which is heterocyclyl optionallysubstituted with halogen, R₁₉, —OR₁₉, —COR₁₉, —SO₂R₁₉, or —CO₂R₁₉,wherein R₁₉ is as defined in Formula (I). Even more preferably, theheterocyclyl group is a 4-, 5-, 6-, 7- or 8-membered saturatedmonocyclic ring comprising one nitrogen heteroatom or a 5-, 6-, 7- or8-membered saturated monocyclic ring comprising one nitrogen atom and 1additional heteroatom selected from —NH, —O—, —S—, —SO— or SO₂—,optionally substituted with halogen, R₁₉, —OR₁₉, —COR₁₉, —SO₂R₁₉, or—CO₂R₁₉, wherein R₁₉ is as defined in Formula (I). Further even morepreferably, the heterocyclyl group is piperidinyl (e.g., piperidin-1-ylor piperidin-4-yl) or piperazinyl (e.g., piperazin-1-yl) groupoptionally substituted with halogen, R₁₉, —OR₁₉, —COR₁₉, —SO₂R₁₉, or—CO₂R₁₉, wherein R₁₉ is as defined in Formula (I). Further even morepreferably, the heterocyclyl group is piperidinyl or piperazinyl groupoptionally substituted with halogen or C₁₋₆alkyl (e.g., methyl). Furthereven more preferably, R₁₂ is hydrogen, R₁₃ is ethyl and R₁₅ is4-methylpiperazin-1-yl. Specifically R₉ is

In a preferred embodiment, R₉ is CONR₁₂R₁₃, wherein R₁₂ is hydrogen, andR₁₃ is cycloalkyl optionally substituted with at least one substituentR₁₅. More preferably, R₁₃ is a C₃-C₈ cycloalkyl optionally substitutedwith at least one substituent R₁₅, Even more preferably, R₁₃ is acyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each optionallysubstituted with at least one substituent R₁₅. In this embodiment, R₁₅is preferably —OR₁₆, or —CO₂R₁₆, or —C₁₋₆alkyl optionally substitutedwith —OR₁₉, wherein R₁₆ and R₁₉ are as defined in Formula (I).Specifically, R₉ is selected from

In a preferred embodiment, R₉ is —CONR₁₂R₁₃, wherein R₁₂ is hydrogen,and R₁₃ is a 5- to 8-membered heterocyclyl comprising 1 or 2 or 3heteroatoms selected from O, NH, S, SO, or SO₂, optionally substitutedwith at least one substituent R₁₅. More preferably, R₁₃ is a 6-memberedheterocyclyl comprising 1 or 2 heteroatoms selected from O or NH,optionally substituted with at least one substituent R₁₅. Even morepreferably, R₁₃ is tetrahydrofuranyl or tetrahydropyranyl, eachoptionally substituted with at least one substituent R₁₅. In thisembodiment, R₁₅ is preferably halogen or —C₁₋₆alkyl. Specifically, R₉ is

In a preferred embodiment, R₉ is CONR₁₂R₁₃, wherein R₁₂ is hydrogen, andR₁₃ is an aryl group selected from phenyl and naphthyl, optionallysubstituted with at least one substituent R₁₅. In this embodiment, R₁₅is preferably halogen, —C₁₋₆alkyl, —OR₁₆, or heterocyclyl optionallysubstituted with halogen, R₁₉, or —OR₁₉, wherein R₁₆ and R₁₉ are asdefined in Formula (I). Specifically, R₉ is selected from

In a preferred embodiment, R₉ is CONR₁₂R₁₃, wherein R₁₇ and R₁₃ togetherwith the nitrogen atom to which they are attached, form a 3- to12-membered saturated, partially or fully unsaturated ring comprising 0,1 or 2 additional heteroatoms independently selected from —NH, —O—, —S—,—SO— or —SO₂—, and said ring is optionally substituted with at least onesubstituent R₁₅.

More preferably, R₉ is —CONR₁₂R₁₃, wherein R₁₂ and R₁₃ together with thenitrogen atom to which they are attached, form a 4-, or 5- or 6- or 7-or 8-membered saturated monocyclic ring comprising 0 additionalheteroatom, and said ring is optionally substituted with at least onesubstituent R₁₈. Specifically, R₁₂ and R₁₃ together with the nitrogenatom to which they are attached, form a azetidinyl, pyrrolidinyl,piperidinyl, azepanyl, or azocanyl ring, preferably, a azetidinyl,pyrrolidinyl, or piperidinyl ring. In this embodiment, R₁₅ is preferablyhalogen, —OR₁₆, —CO₂R₁₆, or —C₁₋₆alkyl optionally substituted with OR₁₉,wherein R₁₆ and R₁₉ are as defined in Formula (I).

More preferably, R₉ is —CONR₁₂R₁₃, wherein R₁₂ and R₁₃ together with thenitrogen atom to which they are attached, form a 5-, 6-, 7- or8-membered saturated monocyclic ring comprising 1 additional heteroatomselected from —NH, —O—, —S—, —SO— or —SO₂—, and said ring is optionallysubstituted with at least one substituent R₁₅. Even more preferably, R₁₇and R₁₃ together with the nitrogen atom to which they are attached, forma morpholinyl or piperazinyl ring, each of which is optionallysubstituted with at least one substituent R₁₅. In this embodiment, R₁₅is preferably hydrogen, halogen, —C₁₋₆alkyl, or cycloalkyl, wherein saidC₁₋₆alkyl, or cycloalkyl are each independently optionally substitutedwith halogen, R₁₉, —OR₁₉, COR₁₉, or —CO₂R₁₉, wherein R₁₉ is as definedin Formula (I).

More preferably, R₉ is CONR₁₂R₁₃, wherein R₁₂ and R₁₃ together with thenitrogen atom to which they are attached, form a 7- to 12-membered(e.g., 7-membered, 8-membered, 9-membered, 10-membered) saturatedbicyclic ring comprising 0 or 1 or 2 additional heteroatoms selectedfrom —N, —O—, —S—, —SO— or —SO₂—, and said ring is optionallysubstituted with at least one substituent R₁₅. Even more preferably, R₁₂and R₁₃ together with the nitrogen atom to which they are attached, forma bicyclic bridged or spiro-ring comprising 0 or 1 or 2 additionalheteroatoms selected from —N, —O—, —S—, —SO— or —SO₂— and optionallysubstituted with at least one substituent R₁₅. The examples of bicyclicbridged or spiro-rings include, but not limited to

For example, R₉ is selected from

In an embodiment of the first aspect, R₁₀ is methoxy, ethoxy, propoxy,or isopropoxy. Preferably, R₁₀ is isopropoxy.

In an embodiment of the first aspect, wherein the carbon atom to whichR₃ and R₄ are attached is in (S)-configuration when R₃ and R₄ aredifferent.

In an embodiment of the first aspect, disclosed herein is a compoundselected from:

or a stereoisomer thereof, or a pharmaceutically acceptable saltthereof.

In an embodiment of the first aspect, disclosed herein is a compoundselected from:

or a pharmaceutically acceptable salt thereof.

The compounds disclosed herein are effective inhibitors against PI3Kδ.Particularly, the compounds disclosed herein have been found to beselective inhibitors against PI3Kδ over PI3Kα, β and/or γ. Moreparticularly, the compounds disclosed herein show better selectivity forPI3Kδ over each of PI3Kα, β and γ. In addition to the above selectivity,the compounds disclosed herein exhibit good pharmacokinetic profile. Forexample, compound 73 disclosed herein exhibits an unexpected longhalf-life.

In the second aspect, disclosed herein is a pharmaceutical compositioncomprising a therapeutically effective amount of the compound disclosedherein, or a stereoisomer thereof or a pharmaceutically acceptable saltthereof, and a pharmaceutically acceptable excipient.

In the third aspect, disclosed herein is a method for treating orpreventing the following a disorders or a disease responsive to theinhibition of PI3Kδ activity by using the compound disclosed herein or astereoisomer thereof or a pharmaceutically acceptable salt thereof; theuse of the compound disclosed herein in the manufacture of a medicamentfor treating or preventing a disorders or a disease responsive to theinhibition of PI3Kδ activity; and the compound disclosed herein or astereoisomer thereof or a pharmaceutically acceptable salt thereof foruse in treating or preventing a disorders or a disease responsive to theinhibition of PI3Kδ activity, wherein the disorder or disease is aninflammatory disorder, an autoimmune disease or a cancer. In someembodiments, the disorder or disease is selected from the groupconsisting of idiopathic thrombocytopenic purpura (ITP), autoimmunehemolytic anemia, vasculitis, systemic lupus erythematosus, lupusnephritis, pemphigus, membranous nephropathy, acute lymphocytichemolytic (ALL), acute myeloid leukemia (AML), chronic lymphocyticleukemia (CLL), Non-Hodgkin lymphoma (NHL), chronic myeloid leukemia(CML), multiple myeloma (MM), hairy cell leukemia, Mantle cell lymphoma(MCL), small lymphocytic lymphoma (SLL), follicular lymphoma,lymphoplasmacytic lymphoma, extranodal marginal zone lymphoma, activatedB-cell like (ABC) diffuse large B cell lymphoma (DLBCL), or germinalcenter B cell (GCB) diffuse large B cell lymphoma (DLBCL), T-celllymphoma, B-cell lymphoma, myelodysplasia syndrome (MDS),myeloproliferative disease (MPD) follicular lymphoma, Waldestrom'smacroglobulinemia (WM), pancreatic cancer, bladder cancer, colorectalcancer, breast cancer, prostate cancer, renal cancer, hepatocellularcancer, lung cancer, ovarian cancer, cervical cancer, gastric cancer,esophageal cancer, head and neck cancer, melanoma, neuroendocrinecancer, CNS cancer, brain cancer, bone cancer, soft tissue sarcoma,non-small cell lung cancer, small-cell lung cancer, colon cancer,systemic lupus erythematosus (SLE), myestenia gravis, rheumatoidarthritis (RA), acute disseminated encephalomyelitis, idiopathicthrombocytopenic purpura, multiple sclerosis (MS), Sjoegren's syndrome,autoimmune hemolytic anemia, asthma, multiple sclerosis, psoriasis,chronic obstructive pulmonary disease or lupus.

Definitions

The following terms have the indicated meanings throughout thespecification:

As used herein, including the appended claims, the singular forms ofwords such as “a”, “an”, and “the”, include their corresponding pluralreferences unless the context clearly dictates otherwise.

The term “or” is used to mean, and is used interchangeably with, theterm “and/or” unless the context clearly dictates otherwise.

The term “alkyl” herein refers to a hydrocarbon group selected fromlinear and branched saturated hydrocarbon groups comprising from 1 to18, such as from 1 to 12, further such as from 1 to 10, more furthersuch as from 1 to 8, or from 1 to 6, or from 1 to 4, carbon atoms.Examples of alkyl groups comprising from 1 to 6 carbon atoms (i.e.,C₁₋₆alkyl) include, but not limited to, methyl, ethyl, 1-propyl orn-propyl (“n-Pr”) 2-propyl or isopropyl (“i-Pr”), 1-butyl or n-butyl(“n-Bu”), 2-methyl-1-propyl or isobutyl (“i-Bu”), 1-methylpropyl ors-butyl (“s-Bu”), 1,1-dimethylethyl or t-butyl (“t-Bu”), 1-pentyl,2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl,3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl,2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl,3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl and3,3-dimethyl-2-butyl groups.

The term “halogen” herein refers to fluoro (F), chloro (Cl), bromo (Br)and iodo (I).

The term “haloalkyl” herein refers to an alkyl group in which one ormore hydrogen is/are replaced by one or more halogen atoms such asfluoro (F), chloro (Cl), bromo (Br), and iodo (I). Examples of thehaloalkyl include haloC₁₋₈alkyl, haloC₁₋₆alkyl or halo C₁₋₄alkyl, butnot limited to —CF₃, —CH₂Cl, —CH₂CF₃, —CCl₂, CF₃, and the like.

The term “alkenyl” herein refers to a hydrocarbon group selected fromlinear and branched hydrocarbon groups comprising at least one C═Cdouble bond and from 2 to 18, such as from 2 to 8, further such as from2 to 6, carbon atoms. Examples of the alkenyl group, e.g., C₂₋₆alkenyl,include, but not limited to ethenyl or vinyl, prop-1-enyl, prop-2-enyl,2-but-1-enyl, but-2-enyl, but-3-enyl, buta-1,3-dienyl,2-methylbuta-1,3-dienyl, hex-1-enyl, hex-2-enyl, hex-3-enyl, hex-4-enyl,and hexa-1,3-dienyl groups.

The term “alkynyl” herein refers to a hydrocarbon group selected fromlinear and branched hydrocarbon group, comprising at least one C≡Ctriple bond and from 2 to 18, such as 2 to 8, further such as from 2 to6, carbon atoms. Examples of the alkynyl group, e.g., C₂₋₆ alkynyl,include, but not limited to ethynyl, 1-propynyl, 2-propynyl (propargyl),1-butyryl, 2-butynyl, and 3-butynyl groups.

The term “alkyloxy” herein refers to an alkyl group as defined abovebonded to oxygen, represented by —Oalkyl. Examples of an alkyloxy, e.g.,C₁₋₆alkyloxy or C₁₋₄alkyloxy includes, but not limited to, methoxy,ethoxy, isopropoxy, propoxy, n-butoxy, tert-butoxy, pentoxy and hexoxyand the like.

The term “cycloalkyl” herein refers to a hydrocarbon group selected fromsaturated and partially unsaturated cyclic hydrocarbon groups,comprising monocyclic and polycyclic (e.g., bicyclic and tricyclic)groups. For example, the cycloalkyl group may comprise from 3 to 12,such as from 3 to 10, further such as 3 to 8, further such as 3 to 6, 3to 5, or 3 to 4 carbon atoms. Even further for example, the cycloalkylgroup may be selected from monocyclic group comprising from 3 to 12,such as from 3 to 10, further such as 3 to 8, 3 to 6 carbon atoms.Examples of the monocyclic cycloalkyl group include cyclopropyl,cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl,1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl,1-cyclohex-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl,cyclodecyl, cycloundecyl, and cyclododecyl groups. In particular,Examples of the saturated monocyclic cycloalkyl group, e.g., C₃₋₈cycloalkyl, include, but not limited to, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups. In apreferred embedment, the cycloalkyl is a monocyclic ring comprising 3 to6 carbon atoms (abbreviated as C₃₋₆ cycloalkyl), including but notlimited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.Examples of the bicyclic cycloalkyl groups include those having from 7to 12 ring atoms arranged as a bicyclic ring selected from [4,4], [4,5],[5,5], [5,6] and [6,6] ring systems, or as a bridged bicyclic ringselected from bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, andbicyclo[3.2.2]nonane. Further Examples of the bicyclic cycloalkyl groupsinclude those arranged as a bicyclic ring selected from [5,6] and [6,6]ring systems, such as

wherein the wavy lines indicate the points of attachment. The ring maybe saturated or have at least one double bond (i.e. partiallyunsaturated), but is not fully conjugated, and is not aromatic, asaromatic is defined herein.

The term “aryl” used alone or in combination with other terms refers toa group selected from:

-   -   a. 5- and 6-membered carbocyclic aromatic rings, e.g., phenyl;    -   b. bicyclic ring systems such as 7 to 12 membered bicyclic ring        systems, wherein at least one ring is carbocyclic and aromatic,        e.g., naphthyl and indanyl; and,    -   c. tricyclic ring systems such as 10 to 15 membered tricyclic        ring systems wherein at least one ring is carbocyclic and        aromatic, e.g., fluorenyl.

The terms “aromatic hydrocarbon ring” and “aryl” are usedinterchangeable throughout the disclosure herein. In some embodiments, amonocyclic or bicyclic aromatic hydrocarbon ring has 5 to 10ring-forming carbon atoms (i.e., C₅₋₁₀ aryl). Examples of a monocyclicor bicyclic aromatic hydrocarbon ring include, but not limited to,phenyl, naphth-1-yl, naphth-2-yl, anthracenyl, phenanthrenyl, and thelike. In some embodiments, the aromatic hydrocarbon ring is anaphthalene ring (naphth-1-yl or naphth-2-yl) or phenyl ring. In someembodiments, the aromatic hydrocarbon ring is a phenyl ring.

The term “heteroaryl” herein refers to a group selected from:

-   -   a. 5-, 6- or 7-membered aromatic, monocyclic rings comprising at        least one heteroatom, for example, from 1 to 4, or, in some        embodiments, from 1 to 3, in some embodiments, from 1 to 2,        heteroatoms, selected from nitrogen (N), sulfur (S) and        oxygen (O) as ring atom(s), with the remaining ring atoms being        carbon;    -   b. 8- to 12-membered bicyclic rings comprising at least one        heteroatom, for example, from 1 to 4, or, in some embodiments,        from 1 to 3, or, in other embodiments, 1 or 2, heteroatoms,        selected from N, O, and S as ring atom(s), with the remaining        ring atoms being carbon and wherein at least one ring is        aromatic and at least one heteroatom is present in the aromatic        ring; and    -   c. 11- to 14-membered tricyclic rings comprising at least one        heteroatom, for example, from 1 to 4, or in some embodiments,        from 1 to 3, or, in other embodiments, 1 or 2, heteroatoms,        selected from N, O, and S as ring atom(s), with the remaining        ring atoms being carbon and wherein at least one ring is        aromatic and at least one heteroatom is present in an aromatic        ring.

In a preferred embodiment, heteroaryl is 5- to 6-membered heteroarylcomprising one nitrogen atom and 0 or 1 additional heteroatom selectedfrom N, O and S, including but not limited to pyridinyl, isoxazolyl, andoxazolyl.

When the total number of S and O atoms in the heteroaryl group exceeds1, those heteroatoms are not adjacent to one another. In someembodiments, the total number of S and O atoms in the heteroaryl groupis not more than 2. In some embodiments, the total number of S and Oatoms in the aromatic heterocycle is not more than 1. When theheteroaryl group contains more than one heteroatom ring member, theheteroatoms may be the same or different. The nitrogen atoms in thering(s) of the heteroaryl group can be oxidized to form N-oxides.

The terms “aromatic heterocyclic ring” and “heteroaryl” are usedinterchangeable throughout the disclosure herein. In some embodiments, amonocyclic or bicyclic aromatic heterocyclic ring has 5-, 6-, 7-, 8-, 9-or 10-ring forming members with 1, 2, 3, or 4 heteroatom ring membersindependently selected from nitrogen (N), sulfur (S) and oxygen (O) andthe remaining ring members being carbon. In some embodiments, themonocyclic or bicyclic aromatic heterocyclic ring is a monocyclic orbicyclic ring comprising 1 or 2 heteroatom ring members independentlyselected from nitrogen (N), sulfur (S) and oxygen (O). In someembodiments, the monocyclic or bicyclic aromatic heterocyclic ring is a5- to 6-membered heteroaryl ring, which is monocyclic and which has 1 or2 heteroatom ring members independently selected from nitrogen (N),sulfur (S) and oxygen (O). In some embodiments, the monocyclic orbicyclic aromatic heterocyclic ring is a 8- to 10-membered heteroarylring, which is bicyclic and which has 1 or 2 heteroatom ring membersindependently selected from nitrogen, sulfur and oxygen.

Examples of the heteroaryl group or the monocyclic or bicyclic aromaticheterocyclic ring include, but are not limited to, (as numbered from thelinkage position assigned priority 1) pyridyl (such as 2-pyridyl,3-pyridyl, or 4-pyridyl), cinnolinyl, pyrazinyl, 2,4-pyrimidinyl,3,5-pyrimidinyl, imidazopyridinyl, isoxazolyl, oxazolyl, thiazolyl,isothiazolyl, thiadiazolyl (such as 1,2,3-thiadiazolyl,1,2,4thiadiazolyl, or 1,3,4-thiadiazolyl), tetrazolyl, thienyl (such asthien-2-yl, thien-3-yl), triazinyl, benzothienyl, furyl or furanyl,benzofuryl, benzoimidazolyl, indolyl, isoindolyl, indolinyl, oxadiazolyl(such as 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, or 1,3,4-oxadiazolyl),phthalazinyl, pyrazinyl, pyridazinyl, pyrrolyl, triazolyl (such as1,2,3-triazolyl, 1,2,4-triazolyl, or 1,3,4-triazolyl), quinolinyl,isoquinolinyl, pyrazolyl, pyrrolopyridinyl (such as1H-pyrrolo[2,3-b]pyridin-5-yl), pyrazolopyridinyl (such as1H-pyrazolo[3,4-b]pyridin-5-yl), benzoxazolyl (such asbenzo[d]oxazol-6-yl), pteridinyl, purinyl, 1-thia-2,4-diazolyl,1-thia-2,5-diazolyl, -thia-3,4-diazolyl, furazanyl (such asfurazan-2-yl, furazan-3-yl), benzofurazanyl, benzothiophenyl,benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl,naphthyridinyl, furopyridinyl, benzothiazolyl (such asbenzo[d]thiazol-6-yl), indazolyl (such as 1H-indazol-5-yl) and5,6,7,8-tetrahydroisoquinoline.

The term “heterocyclic” or “heterocycle” or “heterocyclyl” herein refersto a ring selected from 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11- or12-membered monocyclic, bicyclic and tricyclic, saturated and partiallyunsaturated rings comprising at least one carbon atoms in addition to atleast one heteroatom, such as from 1-4 heteroatoms, further such as from1-3, or further such as 1 or 2 heteroatoms, selected from nitrogen (N),sulfur (S), oxygen (O), —SO— or —SO₂— as ring atom(s).

In some embodiments, a heterocyclyl group is 4-, 5-, 7- or 8-memberedmonocyclic ring with at least one heteroatom selected from N, O and S.In some preferred embodiment, a heterocyclyl group is a 4-, 5-, 6-, 7-or 8-membered saturated monocyclic ring comprising one nitrogenheteroatom. The exemplary heterocyclyl group is azetidinyl,pyrrolidinyl, piperidinyl, azepanyl, and azocanyl. In other embodiment,a heterocyclyl group is a 5-, 6-, 7- or 8-membered saturated monocyclicring comprising one nitrogen atom and 1 additional heteroatom selectedfrom —NH, —O—, —S—, —SO— or SO₂—. The exemplary heterocyclyl group is amorpholino, morpholinyl or piperazinyl ring. In some embodiment, aheterocyclyl group is a 7- to 12-membered saturated bicyclic ringcomprising one nitrogen atom and 0 or 1 or 2 additional heteroatomsselected from —NH, —O—, —S—, —SO— or —SO₂—. In some preferredembodiment, the heterocyclyl group is a bicyclic bridged or spiro-ring.

“Heterocycle” herein also refers to a 5- to 7-membered heterocyclic ringcomprising at least one heteroatom selected from N, O, and S fused with5-, 6-, and/or 7-membered cycloalkyl, carbocyclic aromatic orheteroaromatic ring, provided that the point of attachment is at theheterocyclic ring when the heterocyclic ring is fused with a carbocyclicaromatic or a heteroaromatic ring, and that the point of attachment canbe at the cycloalkyl or heterocyclic ring when the heterocyclic ring isfused with cycloalkyl. “Heterocycle” herein also refers to an aliphaticspirocyclic ring comprising at least one heteroatom selected from N, O,and S, provided that the point of attachment is at the heterocyclicring. The rings may be saturated or have at least one double bond (i.e.partially unsaturated). The heterocycle may be substituted with oxo. Thepoint of the attachment may be carbon or heteroatom in the heterocyclicring. A heterocycle is not a heteroaryl as defined herein. In apreferred embodiment, heterocyclyl is 5- to 6-membered heterocyclylcomprising one nitrogen atom and 0 or 1 additional heteroatom selectedfrom N, O and S, including but not limited to pyrrolyl, dihydropyridine,morpholino, morpholinyl and tetrahydropyranyl.

Examples of the heterocycle include, but not limited to, (as numberedfrom the linkage position assigned priority 1) 1-pyrrolidinyl,2-pyrrolidinyl, 2,4-imidazolidinyl, 2,3-pyrazolidinyl, 1-piperidinyl,3-piperidinyl, 2,5-piperazinyl, pyranyl, morpholinyl, morpholino,2-morpholinyl, 3-morpholinyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl,thietanyl, 1,2-dithietanyl, 1,3-dithietanyl, dihydropyridinyl,tetrahydropyridinyl, thiomorpholinyl, thioxanyl, piperazinyl,homopiperazinyl, homopiperidinyl, azepanyl, oxepanyl, thiepanyl,1,4-oxathianyl, 1,4-dioxepanyl, 1,4-oxathiepanyl, 1,4-oxaazepanyl,1,4-dithiepanyl, 1,4-thiazepanyl and 1,4-diazepanyt 1,4-dithianyl,1,4-azathianyl, oxazepinyl, diazepinyl, thiazepinyl, dihydrothienyl,dihydropyranyl, dihydrofuranyl, tetrahydrofuranyl, tetrahydrothienyl,tetrahydropyranyl, tetrahydrothiopyranyl, 1-pyrrolinyl, 2-pyrrolinyl,3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, 1,4-dioxanyl,1,3-dioxolanyl, pyrazolinyl, pyrazolidinyl, dithianyl, dithiolanyl,pyrazolidinyl, imidazolinyl, pyrimidinonyl, 1,1-dioxo-thiomorpholinyl,3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl andazabicyclo[2.2.2]hexanyl. A substituted heterocycle also includes a ringsystem substituted with one or more oxo moieties, such as piperidinylN-oxide, morpholinyl-N-oxide, 1-oxo-1-thiomorpholinyl and1,1-dioxo-1-thiomorpholinyl.

Compounds disclosed herein may contain an asymmetric center and may thusexist as enantiomers. “Enantiomers” refer to two stereoisomers of acompound which are non-superimposable mirror images of one another.Where the compounds disclosed herein possess two or more asymmetriccenters; they may additionally exist as diastereomers. Enantiomers anddiastereomers fall within the broader class of stereoisomers. All suchpossible stereoisomers as substantially pure resolved enantiomers,racemic mixtures thereof, as well as mixtures of diastereomers areintended to be included. All stereoisomers of the compounds disclosedherein and/or pharmaceutically acceptable salts thereof are intended tobe included. Unless specifically mentioned otherwise, reference to oneisomer applies to any of the possible isomers. Whenever the isomericcomposition is unspecified, all possible isomers are included,

The term “substantially pure” as used herein means that the targetstereoisomer contains no more than 35%, such as no more than 30%,further such as no more than 25%, even further such as no more than 20%,by weight of any other stereoisomer(s). In some embodiments, the term“substantially pure” means that the target stereoisomer contains no morethan 10%, for example, no more than 5%, such as no more than 1%, byweight of any other stereoisomer(s).

When compounds disclosed herein contain olefinic double bonds, unlessspecified otherwise, such double bonds are meant to include both E and Zgeometric isomers.

Some of the compounds disclosed herein may exist with different pointsof attachment of hydrogen, referred to as tautomers. For example,compounds including carbonyl —CH₂C(O)-groups (keto forms) may undergotautomerism to form hydroxyl —CH═C(OH)— groups (enol forms). Both ketoand enol forms, individually as well as mixtures thereof, are alsointended to be included where applicable.

It may be advantageous to separate reaction products from one anotherand/or from starting materials. The desired products of each step orseries of steps is separated and/or purified (hereinafter separated) tothe desired degree of homogeneity by the techniques common in the art.Typically such separations involve multiphase extraction,crystallization from a solvent or solvent mixture, distillation,sublimation, or chromatography. Chromatography can involve any number ofmethods including, for example: reverse-phase and normal phase; sizeexclusion; ion exchange; high, medium and low pressure liquidchromatography methods and apparatus; small scale analytical; simulatedmoving bed (“SMB”) and preparative thin or thick layer chromatography,as well as techniques of small scale thin layer and flashchromatography. One skilled in the art will apply techniques most likelyto achieve the desired separation.

“Diastereomers” refers to stereoisomers of a compound with two or morechiral centers but which are not mirror images of one another.Diastereomeric mixtures can be separated into their individualdiastereomers on the basis of their physical chemical differences bymethods well known to those skilled in the art, such as bychromatography and/or fractional crystallization. Enantiomers can beseparated by converting the enantiomeric mixture into a diastereomericmixture by reaction with an appropriate optically active compound (e.g.,chiral auxiliary such as a chiral alcohol or Mosher's acid chloride),separating the diastereomers and converting (e.g., hydrolyzing) theindividual diastereoisomers to the corresponding pure enantiomers.Enantiomers can also be separated by use of a chiral HPLC column.

A single stereoisomer, e.g., a substantially pure enantiomer, may beobtained by resolution of the racemic mixture using a method such asformation of diastereomers using optically active resolving agents[Eliel, E. and Wilen, S. Stereochemistry of Organic Compounds. New York:John Wiley & Sons, Inc., 1994; Lochmuller, C. H., et al.“Chromatographic resolution of enantiomers: Selective review.” J.Chromatogr., 113(3) (1975): pp. 283-302]. Racemic mixtures of chiralcompounds of the invention can be separated and isolated by any suitablemethod, including: (1) formation of ionic, diastereomeric salts withchiral compounds and separation by fractional crystallization or othermethods, (2) formation of diastereomeric compounds with chiralderivatizing reagents, separation of the diastereomers, and conversionto the pure stereoisomers, and (3) separation of the substantially, pureor enriched stereoisomers directly under chiral conditions. See: Wainer,Irving W., Ed. Drug Stereochemistry: Analytical Methods andPharmacology. New York: Marcel Dekker, Inc., 1993.

“Pharmaceutically acceptable salts” refers to those salts which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of humans and lower animals without undue toxicity,irritation, allergic response and the like, and are commensurate with areasonable benefit/risk ratio. A pharmaceutically acceptable salt may beprepared in situ during the final isolation and purification of thecompounds disclosed herein, or separately by reacting the free basefunction with a suitable organic acid or by reacting; the acidic groupwith a suitable base.

In addition, if a compound disclosed herein is obtained as an acidaddition salt, the free base can be obtained by basifying a solution ofthe acid salt. Conversely, if the product is a free base, an additionsalt, such as a pharmaceutically acceptable addition salt, may beproduced by dissolving the free base in a suitable organic solvent andtreating the solution with an acid, in accordance with conventionalprocedures for preparing acid addition salts from base compounds. Thoseskilled in the art will recognize various synthetic methodologies thatmay be used without undue experimentation to prepare non-toxicpharmaceutically acceptable addition salts.

As defined herein, “a pharmaceutically acceptable salt thereof” includesalts of at least one compound of Formula (I), and salts of thestereoisomers of the compound of Formula (I), such as salts ofenantiomers, and/or salts of diastereomers,

The terms “administration”, “administering”, “treating” and “treatment”herein, when applied to an animal, human, experimental subject, cell,tissue, organ, or biological mean contact of an exogenouspharmaceutical, therapeutic, diagnostic agent, or composition to theanimal, human, subject, cell, tissue, organ, or biological fluid.Treatment of a cell encompasses contact of a reagent to the cell, aswell as contact of a reagent to a fluid, where the fluid is in contactwith the cell. The term “administration” and “treatment” also means invitro and ex vivo treatments, e.g., of a cell, by a reagent, diagnostic,binding compound, or by another cell. The term “subject” herein includesany organism, preferably an animal, more preferably a mammal (e.g., rat,mouse, dog, cat, rabbit) and most preferably a human.

The term “effective amount” or “therapeutically effective amount” refersto an amount of the active ingredient, such as compound that, whenadministered to a subject for treating a disease, or at least one of theclinical symptoms of a disease or disorder, is sufficient to affect suchtreatment for the disease, disorder, or symptom. The “therapeuticallyeffective amount” can vary with the compound, the disease, disorder,and/or symptoms of the disease or disorder, severity of the disease,disorder, and/or symptoms of the disease or disorder, the age of thesubject to be treated, and/or the weight of the subject to be treated.An appropriate amount in any given instance can be apparent to thoseskilled in the art or can be determined by routine experiments. In someembodiments, “therapeutically effective amount” is an amount of at leastone compound and/or at least one stereoisomer thereof, and/or at leastone pharmaceutically acceptable salt thereof disclosed herein effectiveto “treat” as defined above, a disease or disorder in a subject. In thecase of combination therapy, the “therapeutically effective amount”refers to the total amount of the combination objects for the effectivetreatment of a disease, a disorder or a condition.

The term “at least one substituent” disclosed herein includes, forexample, from 1 to 5, such as from 1 to 4, further as 1, 2 or 3,substituents, provided that the valence allows. For example, “at leastone substituent R₁₅” disclosed herein includes from 1 to 4, such as from1 to 3, further as 1 or 2, substituents selected from the list of R₁₅ asdisclosed herein.

The pharmaceutical composition comprising the compound disclosed hereincan be administrated via oral, inhalation, rectal, parenteral or topicaladministration to a subject in need thereof. For oral administration,the pharmaceutical composition may be a regular solid formulation suchas tablets, powder, granule, capsules and the like, a liquid formulationsuch as water or oil suspension or other liquid formulation such assyrup, solution, suspension or the like; for parenteral administration,the pharmaceutical composition may be solution, water solution, oilsuspension concentrate, lyophilized powder or the like. Preferably, theformulation of the pharmaceutical composition is selected from tablet,coated tablet, capsule, suppository, nasal spray or injection, morepreferably tablet or capsule. The pharmaceutical composition can be asingle unit administration with an accurate dosage. In addition, thepharmaceutical composition may further comprise additional activeingredients.

All formulations of the pharmaceutical composition disclosed herein canbe produced by the conventional methods in the pharmaceutical field. Forexample, the active ingredient can be mixed with one or more excipients,then to make the desired formulation. The “pharmaceutically acceptableexcipient” refers to conventional pharmaceutical carriers suitable forthe desired pharmaceutical formulation, for example: a diluent, avehicle such as water, various organic solvents, etc., a filler such asstarch, sucrose, etc. a binder such as cellulose derivatives, alginates,gelatin and polyvinylpyrrolidone (PVP); a wetting agent such asglycerol; a disintegrating agent such as agar, calcium carbonate andsodium bicarbonate; an absorption enhancer such as quaternary ammoniumcompound; a surfactant such as hexadecanol; an absorption carrier suchas Kaolin and soap clay; a lubricant such as talc, calcium stearate,magnesium stearate, polyethylene glycol, etc. In addition, thepharmaceutical composition further comprises other pharmaceuticallyacceptable excipients such as a decentralized agent, a stabilizer, athickener, a complexing agent, a buffering agent, a permeation enhancer,a polymer, aromatics, a sweetener, and a dye.

The term “disease” refers to any disease, discomfort, illness, symptomsor indications, and can be interchangeable with the term “disorder” or“condition”.

Throughout this specification and the claims which follow, unless thecontext requires otherwise, the term “comprise”, and variations such as“comprises” and “comprising” are intended to specify the presence of thefeatures thereafter, but do not exclude the presence or addition of oneor more other features. When used herein the term “comprising” can besubstituted with the term “containing”, “including” or sometimes“having”.

Throughout this specification and the claims which follow the term“C_(n-m)” indicates a range which includes the endpoints, wherein n andm are integers and indicate the number of carbons. Examples includeC₁₋₈, C₁₋₆, and the like.

Unless specifically defined elsewhere in this document, all othertechnical and scientific terms used herein have the meaning commonlyunderstood by one of ordinary skill in the art to which this inventionbelongs.

General Synthesis

Compounds disclosed herein, including salts thereof, can be preparedusing known organic synthesis techniques and can be synthesizedaccording to any of numerous possible synthetic routes.

The reaction for preparing compounds disclosed herein can be carried outin suitable solvents which can be readily selected by one of skill inthe art of organic synthesis. Suitable solvents can be substantiallynon-reactive with the starting materials, the intermediates, or productsat the temperatures at which the reactions are carried out, e.g.,temperatures which can range from the solvent's boiling temperature. Agiven reaction can be carried out in one solvent or mixture of solvents.

The selection of appropriate protecting group, can be readily determinedby one skilled in the art.

Reactions can be monitored according to any suitable method known in theart, such as NMR, UV, HPLC, LC-MS and TLC. Compounds can be purified bya variety of methods, including HPLC and normal phase silicachromatography.

Chiral analytic HPLC was used for the retention time analysis ofdifferent chiral examples, the conditions were divided into the methodsas below according to the column, mobile phase, solvent ration used.

Method A Column CHIRAL CEL OD-H Column size 4.6 cm × 150 cm, 5 umInjection 0.3 ml Mobile phase Hex:EtOH (0.1% DEA) = 90:10 Flow rate 1ml/min Wave length UV 214 nm Temperature 35° C.

Method B Column CHIRAL CEL OD-H Column size 4.6 cm × 150 cm, 5 umInjection 0.3 ml Mobile phase Hex:EtOH (0.1% DEA) = 85:15 Flow rate 1ml/min Wave length UV 214 nm Temperature 35° C.

Method C Column CHIRAL PKA IA Column size 4.6 cm × 150 cm, 5 umInjection 0.3 ml Mobile phase Hex:EtOH (0.1% DEA) = 85:15 Flow rate 1ml/min Wave length UV 214 nm Temperature 35° C.

Method D Column CHIRAL PKA IA Column size 4.6 cm × 150 cm, 5 umInjection 0.3 ml Mobile phase Hex:EtOH (0.1% DEA) = 90:10 Flow rate 1ml/min Wave length UV 214 nm Temperature 35° C.

Method E Column CHIRAL PKA AS-H Column size 4.6 cm × 150 cm, 5 umInjection 0.3 ml Mobile phase Hex:EtOH (0.1% DEA) = 85:15 Flow rate 1ml/min Wave length UV 214 nm Temperature 35° C.

Method F Column CHIRAL PKA AS-H Column size 4.6 cm × 150 cm, 5 umInjection 0.3 ml Mobile phase Hex:EtOH (0.1% DEA) = 90:10 Flow rate 1ml/min Wave length UV 214 nm Temperature 35° C.

Method G Column CHIRAL PKA AS-H Column size 4.6 cm × 150 cm, 5 umInjection 0.3 ml Mobile phase Hex:EtOH (0.1% DEA) = 95:05 Flow rate 1ml/min Wave length UV 214 nm Temperature 35° C.

Method H Column CHIRAL CEL OD-H Column size 4.6 cm × 150 cm, 5 umInjection 0.3 ml Mobile phase Hex:EtOH (0.1% DEA) = 95:5 Flow rate 1ml/min Wave length UV 214 nm Temperature 35° C.

Method I Column CHIRAL PKA AD-H Column size 4.6 cm × 150 cm, 5 umInjection 0.3 ml Mobile phase Hex:EtOH (0.1% DEA) = 90:10 Flow rate 1ml/min Wave length UV 214 nm Temperature 35° C.

Method J Column CHIRAL PKA IA Column size 4.6 cm × 150 cm, 5 umInjection 0.3 ml Mobile phase Hex:EtOH (0.1% DEA) = 80:20 Flow rate 1ml/min Wave length UV 214 nm Temperature 35° C.

Method K Column CHIRAL CEL OD-H Column size 4.6 cm × 150 cm, 5 umInjection 0.3 ml Mobile phase Hex:EtOH (0.1% DEA) = 80:20 Flow rate 1ml/min Wave length UV 214 nm Temperature 35° C.

Method L Column CHIRAL PKA AS-H Column size 4.6 cm × 150 cm, 5 umInjection 0.3 ml Mobile phase Hex:EtOH (0.1% DEA) = 92:08 Flow rate 1ml/min Wave length UV 214 nm Temperature 35° C.

For example, compounds of Formula (I) wherein R₉ is —CONR₁₂R₁₃ can beformed as shown in scheme I. The compound (i) can be halogenated withN-chlorosuccinimide, N-bromosuccinimide or N-iodosuccinamide to givecompound (ii) wherein X¹=Cl, Br, or I, respectively. A Wittig reactionis then carried out from compound (ii) under standard condition (e.g.,Ph₃PCH₃Br/nBuLi or other bases such as NOT) to give compound (iii) whichis carried out under standard Brown reaction condition using BH₃/H₂O₂ togive compound (iv) which was oxidized directly by NaClO/NaClO₂ or Jonesreagent to afford the acid compound (v), the compound (v) was used forcondensation under HOBt or EDCI with suitable amine in Scheme I to givecompound (vi) that was cyclized directly by Tf₂O or POCl₃ to affordcompound (vii) Amination of compound (vii) to give compound (viii) whichis used for CO₂ or CO insertion under nBuLi or palladium catalysts givescompound (ix). Compound (ix) is then reacted with different amines inthe presence of HOBt/EDCI to give compound (x) (i.e., Formula (I)wherein R₉ is —CONR₁₂R₁₃).

The compounds of Formula (I) wherein R₉ is —CONR₁₂R₁₃ can also besynthesized as the route in Scheme H. Compound (i) can be converted tocompound (ii) by using tosmic reagent, followed by hydrolysis underacidic or basic condition to give compound (iii) which is used forcondensation under HOBt or EDCI to give compound (iv). Compound (iv) isthen subject to cyclization under Tf₂O or POCl₃ to give compound (v).Amination of compound (v) gives compound (vi) which is conducted withCO₂ and lithium reagent or CO and palladium catalysts to give compound(vii) that is used for condensation with different amines to givecompound (viii) (i.e., Formula (I) wherein R₉ is —CONR₁₂R₁₃).

The compounds of Formula (I) wherein R₉ is —CONR₁₂R₁₃ can also besynthesized as the route in scheme III. The acid (i.e., compound (i)) issubject to decarboxylative coupling under metal catalysts or otherradical reagents with compound (ii) to give compound (iii) which isconducted with CO₂ and lithium reagent or CO and palladium catalysts togive compound (iv) that is used for condensation with different aminesto give compound (v) (i.e., Formula (I) wherein R₉ is —CONR₁₂R₁₃).

The compounds of Formula (I) wherein R₉ is —CONR₁₂R₁₃ can also besynthesized as the route in Scheme IV. Compound (i) can be chirallyseparated to give chiral acid ii with R or S configuration. Chiralcompound (ii) is used for condensation under HOBt or EDCI to give chiralcompound (iii) which is then subject to cyclization under Tf₂O or POCl₃to give chiral compound (iv). Amination of chiral compound iv giveschiral compound v whish is conducted with CO₂ and lithium reagent or COand palladium catalysts to give chiral compound (vi) that is used forcondensation with different amines to give chiral compound (vii) (i.e.,Formula (I) wherein R₉ is —CONR₁₂R₁₃).

For example, compounds of Formula (I) wherein R₉ is —NR₁₂CONR₁₃R₁₄ canalso be formed as shown in Scheme V. The compound (i) may be subject toCurtius rearrangement to give compound (ii) which is then reacted withtriphosgene and versatile amines to give compound (iii) (i.e., Formula(I) wherein R₉ is —NR₁₂CONR₁₃R₁₄).

For example, compounds of Formula (I) wherein R₉ is —CONR₁₂R₁₃ can alsobe formed as shown in Scheme VI. The halogen of the compound (i) (i.e.,X₁) can be removed by iPrMgBr or iPrMgCl to give compound (ii) which isthen reacted with LDA or LiTMP in the presence of CO₂ to give compound(iii) which is used for the coupling with different amines under HATU,HOBt, EDCI, PyBOP and etc. to give compound (iv) (i.e., Formula (I)wherein R₉ is —CONR₁₂R₁₃).

Abbreviations

-   HOBt Hydroxybenzotriazole-   EDCI 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride-   Tf₂O Trifluoromethanesulfonic anhydride-   HATU    N-[(dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminium    hexafluorophosphate N-oxide-   PyBOP Benzotriazole-1-yl-oxytripyrrolidinophosphonium    hexafluorophosphate-   LDA lithium diisopropyl amide-   LiTMP lithium tetramethylpiperidine-   NBS N-Bromosuccinimide-   DMF N,N-Dimethylformamide-   THF Tetrahydrofuran-   PE Petroleum ether-   EA Ethyl acetate-   aq. aqueous-   TLC thin layer chromatography-   DCM Dichloromethane-   i-PrOH isopropanol-   EtOAc ethyl acetate

EXAMPLE Example 11-(3-(1-(8-amino-1-methylimidazo[1,5-a]pyrazin-3-yl)ethyl)-5-chloro-6-fluoro-2-isopropoxybenzoyl)azetidine-3-carboxylicacid (Compound 1)

Step 1: 1-(5-chloro-4-fluoro-2-hydroxyphenyl)ethan-1-one (1-1)

To a 2 L three-necked flask, equipped with a magnetic stirrer was added4-chloro-3-fluorophenol (160 g, 1.1 mol) and acetyl chloride (129 g,0.69 mol). The mixture was stirred for 1 h. Then aluminum chloride (219g, 1.6 mol) was added into the mixture in portions. The mixture washeated to 160° C. and kept at 150° C. for 2 hrs. The mixture was cooledand diluted with HCl (2 M, 500 mL), The resulting hot liquid was cooledand extracted with ethyl acetate (3×500 mL). The combined organic phasewas washed with water (500 mL) and brine (500 mL), dried over anhydroussodium sulfate, filtered and concentrated to afford 200 g (crude) of1-(5-chloro-4-fluoro-2-hydroxyphenyl)ethan-1-one as a yellow solid, ¹HNMR (400 MHz, CDCl₃) δ 12.48-12.41 (m, 1H), 7.78 (d, J=8.1 Hz, 1H), 6.77(d, J=10.3 Hz, 1H), 2.61 (s, 3H).

Step 2: 1-(3-bromo-5-chloro-4-fluoro-2-hydroxyphenyl)ethan-1-one (1-2)

To a solution of 1-(5-chloro-4-fluoro-2-hydroxyphenyl)ethan-1-one (110g, 412 mmol) in DMF (1 L) was added NBS (11.4 g, 6.40 mmol) in portions.The mixture was stirred at room temperature for 1 h. The mixture wasdiluted with water (3 L), extracted with ethyl acetate (3×1 L), Thecombined organic phase was washed with brine (3×1 L), dried overanhydrous sodium sulfate, filtered and concentrated to afford 150 g(crude) of 1-(5-chloro-4-fluoro-2-hydroxyphenyl)ethan-1-one as a yellowsolid. NMR (400 MHz, CDCl₃) δ 13.21 (d, J=1.8 Hz, 1H), 7.80 (d, J=7.8Hz, 1H), 2.66 (s, 3H).

Step 3: 1-(3-bromo-5-chloro-4-fluoro-2-isopropoxyphenyl)ethan-1-one(1-3)

To a solution of1-(3-bromo-5-chloro-4-fluoro-2-hydroxyphenyl)ethan-1-one (150 g, 560mmol) and 2-iodopropane (143 g, 841 mmol) in DMF (1 L) was added NaHCO₃(71 g, 845 mmol). The mixture was stirred at 60° C. overnight. Themixture was cooled and diluted with water (3 L), extracted with ethylacetate (3×1 L). The combined organic phase was washed with brine (3×1L), dried over anhydrous sodium sulfate, filtered and concentrated. Theresidue was purified by silica gel column chromatography (elution withhexane/ethyl acetate=50/1) to afford 140 g (80%) of1-(3-bromo-5-chloro-4-fluoro-2-isopropoxyphenyl)ethan-1-one as a yellowoil. ¹H NMR (400 MHz, CDCl₃) δ 7.57 (d, J=8.2 Hz, 1H), 4.45-4.39 (m,1H), 2.61 (s, 3H), 1.31 (t, J=6.7 Hz, 6H).

Step 4: 3-bromo-1-chloro-2-fluoro-4-isopropoxy-5-(prop-1-en-2-yl)benzene(1-4)

To a mixture of bromo(methyl)triphenylphosphane (41 g, 11.5 mmol) in THF(400 mL) was added n-BuLi (1.6 M, 72 ml 115 mmol) drop-wise at 0° C. Themixture was stirred at 0° C. for 30 mins. A solution of1-(3-bromo-5-chloro-4-fluoro-2-isopropoxy phenyl)ethan-1-one (30 g, 97mmol) in THF (100 mL) was added to the mixture by dropwise at 0° C. Themixture was stirred at 0° C. for 4 hrs. The mixture was quenched withwater (500 mL), extracted with ethyl acetate (3×200 mL). The combinedorganic phase was washed with brine, dried over anhydrous sodiumsulfate, filtered and concentrated. The residue was purified by silicagel column chromatography (elution with hexane/ethyl acetate=100/1) toafford 5.0 g (17%) of3-bromo-1-chloro-2-fluoro-4-isopropoxy-5-(prop-1-en-2-yl)benzene as ayellow oil, ¹H NMR (400 MHz, CDCl₃) δ 7.21-7.17 (m, 1H), 5.20-5.16 (m,1H), 5.13-5.10 (m, 1H), 4.54-4.44 (m, 1H), 2.10-2.08 (m, 3H), 1.29-1.25(m, 6H).

Step 5: 2-(3-bromo-5-chloro-4-fluoro-2-isopropoxyphenyl)propan-1-ol(1-5)

To a 3 L flask equipped with a magnetic stirrer was added3-bromo-1-chloro-2-fluoro-4-isopropoxy-5-(prop-1-en-2-yl)benzene (170 g,553 mmol) and BH₃·THF (1M, 1660 mL). The mixture was stirred overnightat room temperature. The mixture was quenched with water (100 mL)carefully. A solution of NaOH (22 g, 550 mmol) in water (400 mL) wasadded to the mixture by dropwise at 0° C., then H₂O₂ (30%, 188 mL) wasadded to the mixture by dropwise at 0° C. The mixture was stirred atroom temperature for 4 hrs. The mixture was quenched with NaHSO₃solution (1 L) carefully in ice-water bath. Then the mixture wasextracted with ethyl acetate (3×1000 mL). The combined organic phase waswashed with brine, dried over anhydrous sodium sulfate, filtered andconcentrated to afford 200 g (crude) of2-(3-bromo-5-chloro-4-fluoro-2-isopropoxyphenyl)propan-1-ol as a yellowoil.

Step 6: 2-(3-bromo-5-chloro-4-fluoro-2-isopropoxyphenyl)propanoic acid(1-6)

To a solution of2-(3-bromo-5-chloro-4-fluoro-2-isopropoxyphenyl)propan-1-ol (200 g, 614mmol) and TEMPO (0.8 g, 5.1 mmol) in acetonitrile (1 L) was addedphosphate buffer (PH=6.7, 1 L). The mixture was cooled in water bath. Amixture of NaClO (10%, 500 mL) and NaClO₂ (180 g in water 500 mL) wasadded dropwise to the mixture during 30 mins. The mixture was stirredfor 2 hrs, then the mixture was extracted with ethyl acetate (2×1000mL). The combined organic phase was treated with HCl (2M, 500 mL), theorganic phase was separated, washed with brine, dried over anhydroussodium sulfate, filtered and concentrated. The residue was trituratedwith acetonitrile (150 mL), the precipitate was collected by filtrationto afford 90 g (43%) of2-(3-bromo-5-chloro-4-fluoro-2-isopropoxyphenyl)propanoic acid as awhite solid. ¹H NMR (400 MHz, DMSO-d6) δ 12.55 (s, 1H), 7.51 (d, J=8.4Hz, 1H). 4.60-4.50 (m, 1H), 4.03 (q, 7.2 Hz, 1H), 2.08 (s, 3H), 1.37 (d,J=7.3 Hz, 3H), 1.31-1.27 (m, 6H). MS (ESI) m/e [M−H]⁻ 336.9, 338.9.

Step 7:2-(3-bromo-5-chloro-4-fluoro-2-isopropoxyphenyl)-N-(1-(3-chloropyrazin-2-yl)ethyl)propanamide(1-7)

To a solution of2-(3-bromo-5-chloro-4-fluoro-2-isopropoxyphenyl)propanoic acid (13.0 g,38.3 mmol) and 1-(3-chloropyrazin-2-yl)ethan-1-amine (6.0 g, 38.1 mmol)in dichloromethane (150 mL) were added Et₃N (11.6 g, 114.6 mmol), HOBT(6.2 g, 45.9 mmol) and EDCI (8.8 g, 45.9 mmol), The mixture was stirredfor 3 hrs. The mixture was diluted with water (300 mL), extracted withdichloromethane (3×100 nit). The combined organic phase was dried andconcentrated. The residue was purified by silica gel columnchromatography (elution with dichloromethane/ethyl acetate from 20/1 to5/1) to afford 11.4 g (62%) of2-(3-bromo-5-chloro-4-fluoro-2-isopropoxyphenyl)-N-(1-(3-chloropyrazin-2-yl)ethyl)propanamideas a yellow solid. ¹H NMR (400 MHz, CDCl₃) δ 8.30 (d, J=2.4 Hz, 1H),8.26 (d, J=2.4 Hz, 1H), 7.31 (d, J=8.1 Hz, 1H), 6.96 (d, J=7.6 Hz, 1H),5.47-5.39 (m, 1H), 4.73-4.63 (m, 1H), 4.15-4.07 (m, 1H), 1.51-1.42 (m,9H), 1.32 (d, J=6.2 Hz, 3H). MS (EST) m/e [M+1]⁺ 478.0, 480.0.

Step 8:3-(1-(3-bromo-5-chloro-4-fluoro-2-isopropoxyphenyl)ethyl)-8-chloro-1-methylimidazo[1,5-a]pyrazine(1-8)

To a solution of2-(3-bromo-5-chloro-4-fluoro-2-isopropoxyphenyl)-N-(1-(3-chloropyrazin-2-yl)ethyl)propanamide(11.4 g, 23.8 mmol) in dichloromethane (130 mL) was added a solution ofTf₂O in dichloromethane (30 mL) dropwise. Then a solution of pyridine(9.4 g, 119 mmol) in dichloromethane (40 mL) was added by dropwise tothe mixture. The mixture was stirred at room temperature for 1 h. Themixture was quenched with water (200 mL), extracted with dichloromethane(3×100 mL). The combined organic phase was dried and concentrated. Theresidue was purified by silica gel column chromatography (elution withdichloromethane/ethyl acetate from 20/1 to 5/1) to afford 8.0 g (73%) of3-(1-(3-bromo-5-chloro-4-fluoro-2-isopropoxyphenyl)ethyl)-8-chloro-1-methylimidazo[1,5-a]pyrazineas a yellow solid. ¹H NMR (400 MHz, CDCl₃) δ 7.57 (d, J=4.8 Hz, 1H),7.30 (d, J=7.8 Hz, 1H), 7.15 (d, J=4.6 Hz, 1H), 4.84-4.69 (m, 2H), 2.82(s, 3H), 1.86 (d, J=7.0 Hz, 3H), 1.53 (d, J=6.1 Hz, 3H), 1.38 (d, J=6.1Hz, 3H). MS (ESI) m/e [M+1]+459.9, 462.0.

Step 9:3-(1-(3-bromo-5-chloro-4-fluoro-2-isopropoxyphenyl)ethyl)-1-methylimidazo[1,5-a]pyrazin-8-amine(1-9)

A mixture of3-(1-(3-bromo-5-chloro-4-fluoro-2-isopropoxyphenyl)ethyl)-8-chloro-1-methylimidazo[1,5-a]pyrazine(1.01 g, 2.2 mmol) and NH₃ in iPrOH (20 mL) in a steel tube was stirredat 90°C for 48 hrs. After completion, the mixture was evaporated invacuo. The residue was added 50 mL ethyl acetate, washed with water (30mL×2), dried over Na₂SO₄, filtered and evaporated in vacuo to give thecrude product, then the crude product was stirred in petroleum (250 mL)and filtrated to give the product (0.96 g, 98.3%) as a white solid.

Step 10:3-(1-(8-amino-1-methylimidazo[1,5-a]pyrazin-3-yl)ethyl)-5-chloro-6-fluoro-2-isopropoxybenzoicacid (1-10)

To a solution of compound 1-9 (1.15 g, 2.6 mmol) in THF (50 mL) wasadded n-BuLi (2.4 M, 3.5 mL) dropwise at −78° C. The mixture was stirredfor 10 min, CO₂ gas was bubbled into the mixture. The mixture wasstirred for 30 m. The mixture was warmed to room temperature andquenched with water (50 mL), washed with ethyl acetate (30 mL), Thewater layer was separated, acidified with concentrated HCl to pH=1 andconcentrated to afford 1.1 g (crude) of3-(1-(8-amino-1-methylimidazo[1,5-a]pyrazin-3-yl)ethyl)-5-chloro-6-fluoro-2-isopropoxybenzoicacid as a yellow solid. MS (ESI) m/e [M+H]⁺ 407.1.

Step 11: Methyl1-(3-(1-(8-amino-1-methylimidazo[1,5-a]pyrazin-3-yl)ethyl)-5-chloro-6-fluoro-2-isopropoxybenzoyl)azetidine-3-carboxylate(1-11)

To a solution of compound 1-10 (200 mg, crude) and methylazetidine-3-carboxylate hydrochloride (75 mg, 0.5 mmol) in DMF (20 mL)was added Et₃N (1.0 g, 10 mmol), and PyBOP (260 mg, 0.5 mmol). Themixture was stirred for 2 hrs. The mixture was diluted with water (50mL), extracted with ethyl acetate (3×30 mL). The combined organic phasewas washed with water (50 mL), brine (50 mL), dried over anhydroussodium sulfate, filtered and concentrated to afford 100 mg (crude) ofmethyl1-(3-(1-(8-amino-1-methylimidazo[1,5-a]pyrazin-3-yl)ethyl)-5-chloro-6-fluoro-2-isopropoxybenzoyl)azetidine-3-carboxylateas a yellow oil. MS (ESI) m/e [M+H]⁺ 504.2.

Step 12:1-(3-(1-(8-amino-1-methylimidazo[1,5-a]pyrazin-3-yl)ethyl)-5-chloro-6-fluoro-2-isopropoxybenzoyl)azetidine-3-carboxylicacid trifluoroacetate (1-12)

To a solution of compound 1-11 (100 mg, crude) in MeOH (10 mL) was addedNaOH aqueous solution (1M, 10 mL). The mixture was stirred for 6 hrs,and concentrated under vacuum. The residue was purified by prep-HPLC toafford 30 mg (25%) of1-(3-(1-(8-amino-1-methylimidazo[1,5-a]pyrazin-3-yl)ethyl)-5-chloro-6-fluoro-2-isopropoxybenzoyl)azetidine-3-carboxylicacid trifluoroacetate. ¹H NMR (400 MHz, DMSO-d6) δ 8.51 (brs, 2H),7.53-7.43 (m, 2H), 6.93 (d, J=5.9 Hz, 0.5H), 6.86 (d, J=5.9 Hz, 0.5H),4.88-4.80 (m, 1H), 4.44-4.36 (m, 1H), 4.23 (t, J=9.5 Hz, 1H), 4.11-4.01(m, 2H), 3.96-3.85 (m, 1H), 3.50-3.37 (m, 1H), 2.64 (s, 3H), 1.64 (t,J=6.6 Hz, 3H), 1.26-1.11 (m, 6H). MS (EST) m/e [M+H]⁺490.1.

Example 21-(3-(1-(8-amino-1-methylimidazo[1,5-a]pyrazin-3-yl)ethyl)-5-chloro-6-fluoro-2-isopropoxybenzamido)cyclopropane-1-carboxylicAcid (Compound 2)

The desired compound was prepared from compound 1-10 and ethyl1-aminocyclopropane-1-carboxylate in a similar manner to compound 1 inExample 1. ¹H NMR (400 MHz, DMSO-d6) δ 9.05 (s, 1H), 8.60 (s, 2H),7.54-7.47 (m, 2H), 6.95 (d, J=5.8 Hz, 1H), 4.85 (q, J=7.0 Hz, 1H),4.78-4.67 (m, 1H), 2.64 (s, 3H), 1.61 (d, J=7.0 Hz, 3H), 1.46-1.38 (m,1H), 1.15 (d, J=5.9 Hz, 3H), 1.10-1.01 (m, 5H). MS (ESI) m/e[M+H]⁺490.1.

Example 3(3-(1-(8-amino-1-methylimidazo[1,5-a]pyrazin-3-yl)ethyl)-5-chloro-6-fluoro-2-isopropoxyphenyl)(3-hydroxyazetidin-1-yl)methanone(Compound 3)

The desired compound was prepared from compound 1-10 and azetidin-3-olin a similar manner to compound 1-11 in Example 1. ¹H NMR (400 MHz,DMSO-d6) δ 7.39-7.33 (m, 1H), 7.24-7.19 (m, 1H), 6.87-6.78 (m, 1H), 6.46(s, 2H), 5.90-5.80 (m, 1H), 4.81-4.73 (m, 1H), 4.57-4.45 (m, 1H),4.42-4.30 (m, 1H), 4.28-4.19 (m, 1H), 4.07-3.99 (m, 1H), 3.81-3.67 (m,2H), 2.57 (s, 3H), 1.70-1.55 (m, 3H), 1.40-1.15 (m, 6H). MS (ESI) m/e[M+1]⁺462.1.

Example 4(3-(1-(8-amino-1-methylimidazo[1,5-a]pyrazin-3-yl)ethyl)-5-chloro-6-fluoro-2-isopropoxyphenyl)(morpholino)methanone(Compound 4)

The desired compound was prepared from compound 1-0 and morpholine in asimilar manner to compound 1-11 in Example 1. ¹H NMR (400 MHz, DMSO-d6)δ 7.46 (d, J=8.7 Hz, 0.3H), 7.36 (d, J=8.5 Hz, 0.7H), 7.26 (d, J=5.0 Hz,0.3H), 7.17 (d, J==5.0 Hz, 0.7H), 6.86 (d, J=5.0 Hz, 0.3H), 6.82 (d,J==5.0 Hz, 0.7H), 6.53-6.42 (m, 2H), 4.81-4.70 (m, 1H), 4.45-4.35 (m,0.7H), 4.31-4.21 (m, 0.3H), 3.79-3.55 (m, 4H), 3.55-3.46 (m, 2H),3.15-2.99 (m, 2H), 2.59-2.55 (m, 3H), 1.67 (d, J=7.1 Hz, 2H), 1.56 (d,J=7.1 Hz, 1H), 1.25 (t, J=6.5 Hz, 4H), 1.17 (d, J=6.1 Hz, 1H), 0.99 (d,J=6.0 Hz, 1H). MS (ESI) m/e [M+1]⁺476.1.

The compound 4 was separated by chiral column to give compound 4A (peak1, S or R, retention time (RT) at 8.78 min in chiral analysis, Method A)and compound 4B (peak 2, R or S, retention time (RT) at 8.19 min inchiral analysis, Method A).

Compound 4A: ¹H NMR (400 MHz, DMSO-d6) δ 7.46 (d, J=8.7 Hz, 0.3H), 7.36(d, J=8.5 HZ, 0.7H), 7.26 (d, J=5.0 Hz, 0.3H), 7.17 (d, J==5.0 Hz,0.7H), 6.86 (d, J=5.0 Hz, 0.3H), 6.82 (d, J=5.0 Hz, 0.7H), 6.53-6.42 (m,2H), 4.81-4.70 (m, 1H), 4.45-4.35 (m, 0.7H), 4.31-4.21 (m, 0.3H),3.79-3.55 (m, 4H), 3.55-3.46 (m, 2H), 3.15-2.99 (m, 2H), 2.59-2.55 (m,3H), 1.67 (d, J=7.1 Hz, 2H), 1.56 (d, J=7.1 Hz, 1H), 1.25 (t, J=6.5 Hz,4H), 1.17 (d, J=6.1 Hz, 1H), 0.99 (d, J=6.0 Hz, 1H). MS (ESI) m/e[M+1]⁺476.1.

Compound 4B: ¹H NMR (400 MHz, DMSO-d6) δ 7.46 (d, J=8.7 Hz, 0.3H), 7.35(d, J=8.5 Hz, 0.7H), 7.25 (d, J=5.1 Hz, 0.3H), 7.16 (d, J=5.0 Hz, 0.7H),6.85 (d, J=5.0 Hz, 0.3H), 6.82 (d, J=5.0 Hz, 0.7H), 6.53-6.42 (m, 2H),4.81-4.70 On, 1H), 4.45-4.35 (m 0.7H), 4.31-4.21 (m, 0.3H), 3.79-3.55(m, 4H), 3.55-3.45 (m, 2H), 3.14-3.00 (m, 2H), 2.59-2.55 (m, 3H), 1.67(d, J=7.1 Hz, 2H), 1.56 (d, J=7.1 Hz, 1H), 1.25 (t, J=6.5 Hz, 4H), 1.17(d, J=6.1 Hz, 1H), 0.99 (d, J=6.0 Hz, 1H). MS (ESI) m/e [M+1]⁺476.1.

The chiral separation conditions are shown below.

Column CHIRALPAK IG Column size 2 cm × 25 cm, 5 um Injection 1 ML Mobilephase Hex(0.2% IPAmine):IPA = 70:30 Flow rate 20 mL/min Wave length UV220 nm Temperature 25° C. Sample solution 15.3 mg/mL in DCM:EtOH = 1:2Prep-HPLC equipment Prep-Gilson-HPLC

Example 53-(1-(8-amino-1-methylimidazo[1,5-a]pyrazin-3-yl)ethyl)-5-chloro-6-fluoro-N-(1-(hydroxymethyl)cyclopropyl)-2-isopropoxybenzamide(Compound 5)

The desired compound was prepared from compound 1-10 and(1-aminocyclopropyl)methanol in a similar manner to compound 1-11 inExample 1. ¹H NMR (400 MHz, DMSO-d6) δ 8.92 (s, 1H), 7.36 (d, J=8.6 Hz,1H), 7.23 (d, J=5.1 Hz, 1H), 6.85 (d, J=5.0 Hz, 1H), 6.44 (s, 2H), 4.75(q, J=6.9 Hz, 1H), 4.67 (t, J=5.6 Hz, 1H), 4.49 (dt, J=12.1, 6.0 Hz,1H), 3.55 (d, J=5.7 Hz, 2H), 2.56 (s, 3H), 1.56 (d, J=7.1 Hz, 3H), 1.18(d, J=6.0 Hz, 3H), 1.08 (d, J=6.0 Hz, 3H), 0.78 (t, J=5.7 Hz, 2H), 0.61(t, J=5.7 Hz, 2H). MS (ESI) m/e [M+1]⁺476.4.

The compound 5 was separated by chiral column to give compound 5A (peak1, S, retention time (RT) at 4.80 min in chiral analysis, Method A) andcompound 5B (peak 2, retention time (RT) at 6.11 min in chiral analysis,Method A).

Compound 5A: ¹H NMR (400 MHz, DMSO-d6) δ 8.92 (s, 1H), 7.36 (d, J=8.6Hz, 1H), 7.23 (d, J=5.1 Hz, 1H), 6.85 (d, J=5.0 Hz, 1H), 6.44 (s, 2H),4.75 (q, J=6.9 Hz, 1H), 4.67 (t, J=5.6 Hz, 1H), 4.49 (dt, J=12.1, 6.0Hz, 1H), 3.55 (d, J=5.7 Hz, 2H), 2.56 (s, 3H), 1.56 (d, J=7.1 Hz, 3H),1.18 (d, J=6.0 Hz, 3H), 1.08 (d, J=6.0 Hz, 3H), 0.78 (t, J=5.7 Hz, 2H),0.61 (t, J=5.7 Hz, 2H). MS (ESI) m/e [M+1]⁺ 476.4. The absolute (S)configuration of chiral center in compound 5A was confirmed by x-rayanalysis of single crystal.

Compound 5B: ¹H NMR (400 MHz, DMSO-d6) δ 8.92 (s, 1H), 7.36 (d, J=8.6Hz, 1H), 7.23 (d, J=5.1 Hz, 1H), 6.85 (d, J=5.0 Hz, 1H), 6.44 (s, 2H),4.75 (q, J=6.9 Hz, 1H), 4.67 (t, J=5.6 Hz, 1H), 4.49 (dt, J=12.1, 6.0Hz, 1H), 3.55 (d, J=5.7 Hz, 2H), 2.56 (s, 3H), 1.56 (d, J=7.1 Hz, 3H),1.18 (d, J=6.0 Hz, 3H), 1.08 (d, J=6.0 Hz, 3H), 0.78 (t, J=5.7 Hz, 2H),0.61 (t, J=5.7 Hz, 2H). MS (ESI) m/e [M+1]⁺476.4.

The chiral separation conditions are shown below.

Column CHIRAL ART Cellulose-SB Column size 2 cm × 25 cm, 5 um Injection0.4 ML Mobile phase Hex:EtOH = 80:20 Flow rate 20 mL/min Wave length UV220 nm Temperature 25° C. Sample solution 21 mg/mL in EtOH:DCM = 3:1Prep-HPLC equipment Prep-Gilson-HPLC

Example 6

(3-(1-(8-amino-1-methylimidazo[1,5-a]pyrazin-3-yl)ethyl)-5-chloro-6-fluoro-2-isopropoxyphenyl)((S)-3-hydroxypyrrolidin-1-yl)methanone(Compound 6)

The desired compound was prepared from compound 1-10 and(S)-pyrrolidin-3-ol in a similar manner to compound 1-11 in Example 1.¹H NMR (400 MHz, DMSO-d6) δ 7.42-7.27 (m, 1H), 7.26-7.13 (m, 1H),6.87-6.75 (m, 1H), 6.49-6.42 (m, 2H), 5.08-4.99 (m, 1H), 4.82-4.71 (m,1H), 4.48-4.30 (m, 1.5H), 4.30-4.19 (m, 0.5H), 3.68-3.38 (m, 2H),3.23-3.04 (m, 1H), 3.03-2.92 (m, 1H), 2.60-2.55 (m, 3H), 2.04-1.72 (m,2H), 1.66 (d, J=6.8 Hz, 2H), 1.54 (d, J=6.5 Hz, 1H), 1.29-1.13 (m, 5H),0.92 (dd, J=12.8, 6.0 Hz, 1H). MS (ESI) m/e [M+1]⁺ 476.1.

Example 7

(3-(1-(8-amino-1-methylimidazo[1,5-a]pyrazin-3-yl)ethyl)-5-chloro-6-fluoro-2-isopropoxyphenyl)(4-hydroxypiperidin-1-yl)methanone(Compound 7)

The desired compound was prepared from compound 1-10 and piperidin-4-olin a similar manner to compound 1-11 in Example 1. ¹H NMR (400 DMSO-d6)δ 7.36-7.2 (m, 1H), 7.17-7.12 (m, 1H), 6.84 (dd, J=5.0, 1.9 Hz, 0.3H),6.79-6.75 (m, 0.7H), 6.17 (s, 2H), 4.80-4.68 (m, 1H), 4.64-4.28 (m, 2H),4.17-4.09 (m, 0.4H), 4.07-3.96 (m, 0.4H), 3.95-3.87 (m, 0.3H), 3.84-3.66(m, 1H), 3.48-3.39 (m, 0.3H), 3.39-3.24 (m, 0.7H), 3.24-3.12 (m, 1H),2.98-2.87 (m, 1H), 2.58 (s, 3H); 1.88-1.73 (m, 1H), 1.71-1.65 (m, 3H),1.58 (d, J=7.0 Hz, 1H), 1.48-1.35 (m, 2H); 1.28 (d, J=6.1 Hz, 1H),1.27-1.19 (m, 3.5H), 1.17 (d, J=6.1 Hz, 0.5H), 1.04 (dd, J=9.6, 6.1 Hz,1H). MS (ESI) m/e [M+1]+490.1.

Example 83-(1-(8-amino-1-methylimidazo[1,5-a]pyrazin-3-yl)ethyl)-5-chloro-6-fluoro-2-isopropoxy-N-(2-methoxyethyl)benzamide(Compound 8)

The desired compound was prepared from compound 1-10 and2-methoxyethan-1-amine in a similar manner to compound 1-11 inExample 1. ¹H NMR (400 MHz, DMSO-d6) δ 8.78 (t, J=5.4 Hz, 1H), 7.38 (d,J=8.6 Hz, 1H), 7.25 (d, J=5.0 Hz, 1H), 6.85 (d, J=5.0 Hz, 1H), 6.48 (s,2H), 4.77 (q, J=7.1 Hz, 1H), 4. 52-4.45 (m, 1H), 3.45-3.37 (m, 4H), 3.25(s, 3H), 2.57 (s, 3H), 1.58 (d, J=7.1 Hz, 3H), 1.18 (d, J=6.0 Hz, 3H),1.08 (d, J=6.0 Hz, 3H). MS (ESI) m/e [M+1]⁺ 464.1.

Example 93-(1-(8-amino-1-methylimidazo[1,5-a]pyrazin-3-yl)ethyl)-5-chloro-6-fluoro-N—((R)-2-hydroxypropyl)-2-isopropoxybenzamide(Compound 9)

The desired compound was prepared from compound 1-10 and(R)-1-aminopropan-2-ol in a similar manner to compound 1-11 inExample 1. ¹H NMR (400 MHz, DMSO-d6) δ 8.65 (t, J 5.6 Hz, 1H), 7.38 (d,J=8.5 Hz, 1H), 7.24 (d, J=5.0 Hz, 1H), 6.85 (d, J=4.4 Hz, 1H), 6.42 (s,2H), 4.81-4.73 (m, 1H), 4.69 (d, J=2.8 Hz, 1H), 4.53-4.42 (m, 1H),3.78-3.68 (m, 1H), 3.27-3.18 (m, 1H), 3.15-3.05 (m, 1H), 2.56 (s, 3H),1.58 (d, J=6.9 Hz, 3H), 1.18 (d, J=6.0 Hz, 3H), 1.11-1.05 (m, 6H). MS(ESI) m/e [M+1]⁺464.1.

Example 103-(1-(8-amino-1-methylimidazo[1,5-a]pyrazin-3-yl)ethyl)-5-chloro-6-fluoro-N-((1-hydroxycyclopropyl)methyl)-2-isopropoxybenzamide(Compound 10)

The desired compound was prepared from compound 1-10 and1-(aminomethyl)cyclopropan-1-ol in a similar manner to compound 1-11 inExample 1. ¹H NMR (400 MHz, DMSO-d6) δ 8.71 (t, J=5.7 Hz, 1H), 7.37 (d,J=8.6 Hz, 1H), 7.24 (d, J=5.0 Hz, 1H), 6.85 (d, J=5.1 Hz, 1H), 6.42 (s,2H), 5.26 (s, 1H), 4.77 (q, J=6.9 Hz, 1H), 4.59-4.52 (m, 1H), 3.40 (d,J=5.8 Hz, 2H), 2.57 (s, 3H), 1.58 (d, J=7.1 Hz, 3H), 1.19 (d, J=6.0 Hz,3H), 1.09 (d, J=6.0 Hz, 3H), 0.54 (s, 4H). MS (ESI) m/e [M+1]⁺476.1.

Example 113-(1-(8-amino-1-methylimidazo[1,5-a]pyrazin-3-yl)ethyl)-5-chloro-N-cyclopropyl-6-fluoro-2-isopropoxybenzamide(Compound 11)

The desired compound was prepared from compound 1-10 andcyclopropylamine in a similar manner to compound 1-11 in Example 1. ¹HNMR 400 MHz, DMSO-d6) δ 8.73 (d, J=4.1 Hz, 1H), 7.40 (d, J=8.6 Hz, 1H),J=5.0 Hz, 1H), 6.86 (d, J=4.9 Hz, 1H), 6.43 (5, 2H), 4.76 (q, J=7.0 Hz,1H), 4.46-4.37 (m, 1H), 2.85-2.76 (m, 1H), 0.56 (s, 3H) 1.57 (d, J=7.0Hz, 3H), 1.19 (d, J=6.0 Hz, 3H), 1.07 (d, J=6.0 Hz, 3H), 0.70 (q, J=6.5Hz, 2H), 0.49-0.43 (m, 2H). MS (ESI) m/e [M+1]⁺446.1.

Example 123-(1-(8-amino-1-methylimidazo[1,5-a]pyrazin-3-yl)ethyl)-5-chloro-6-fluoro-2-isopropoxy-N-phenylbenzamide(Compound 12)

The desired compound was prepared from compound 1-10 and aniline in asimilar manner to compound 1-11 in Example 1. ¹H NMR (400 MHz, DMSO-d6)δ 10.72 (s, 1H), 7.65 (d, J=8.0 Hz, 2H), 7.52 (d, J=8.6 Hz, 1H), 7.36(t, J=7.8 Hz, 2H), 7.30 (d, J=5.0 Hz, 1H), 7.13 (t, J=7.3 Hz, 1H), 6.87(d, J=4.9 Hz, 1H), 6.43 (s, 2H), 4.81 (q, J=6.8 Hz, 1H), 4.49-4.39 (m,1H), 2.57 (s, 3H), 1.61 (d, J=7.0 Hz, 3H), 1.19 (d, J=6.0 Hz, 3H), 1.05(d, J=6.0 Hz, 3H). MS (ESI) m/e [M+1]⁺482.1.

Example 13(3-(1-(8-amino-1-methylimidazo[1,5-a]pyrazin-3-yl)ethyl)-5-chloro-6-fluoro-2-isopropoxyphenyl)(4,4-difluoropiperidin-1-yl)methanone(Compound 13)

The desired compound was prepared from compound 1-0 and4,4-difluoropiperidine in a similar manner to compound 1-11 inExample 1. ¹H NMR (400 MHz, DMSO-d6) δ 7.51-7.46 (m, 0.3H), 7.42-7.35(m, 0.7H), 7.28-7.23 (m, 0.3H), 7.20-7.14 (m, 0.7H), 6.88-6.81 (m, 1H),6.45 (s, 2H), 4.81-4.70 (m, 1H), 4.34-4.34 (m, 1H), 4.04-3.94 (m, 1H),3.84-3.72 (m, 1H), 3.65-3.55 (m, 1H), 3.22-3.15 (m, 1H), 2.57 (s, 3H)2.18-1.87 (m, 4H), 1.71-1.65 (m, 2H), 1.60-1.54 (m, 1H), 1.27-1.20 (m,4H), 1.17-1.12 (m, 1H), 1.00-0.95 (m, 1H). MS (ESI) m/e [M+1]⁺510.1.

The compound 13 was separated by chiral column to give compound 13A(peak 1, S or R, retention time (RT) at 8.65 miry in chiral analysis,Method H) and compound 13B (peak 2, R or S, retention time (RT) at 11.06min in chiral analysis, Method H).

Compound 13A: ¹H NMR (400 MHz, DMSO-d6) δ 7.51-7.46 (m, 0.3H), 7.42-7.35(m, 0.7H), 7.28-7.23 (m, 0.3H), 7.20-7.14 (m, 0.7H), 6.88-6.81 (m, 1H),6.45 (s, 2H), 4.81-4.70 (m, 1H), 4.34-4.34 (m, 1H), 4.04-3.94 (m, 1H),3.84-3.72 (m, 1H), 3.65-3.55 (m, 1H), 3.22-3.15 (m, 1H), 2.57 (s, 3H),2.18-1.87 (m, 4H), 1.71-1.65 (m, 2H), 1.60-1.54 (m, 1H), 1.27-1.20 (m,4H), 1.17-1.12 (m, 1H), 1.00-0.95 (m, 1H). (ESI) m/e [M+1]⁺510.1.

Compound 13B: ¹H NMR (400 MHz, DMSO-d6) δ 7.48 (d, J=8.6 Hz, 0.3H), 7.38(d, J=8.5 Hz, 0.7H), 7.25 (d, J=4.7 Hz, 0.3H), 7.16 (d, J=4.9 Hz, 0.7H),6.87-6.81 (m, 1H), 6.44 (s, 2H), 4.80-4.70 (m, 1H), 4.44-4.34 (m, 1H),4.03-3.93 (m, 1H), 3.84-3.72 (m, 1H), 3.65-3.55 (m, 1H), 3.22-3.15 (m,1H), 2.57 (s, 3H), 2.18-1.86 (m, 4H), 1.67 (d, J=7.0 Hz, 2H), 1.56 (d,J=7.1 Hz, 1H), 1.23 (t, J=5.7 Hz, 4H), 1.14 (d, J=6.0 Hz, 1H), 0.97 (d,J=5.9 Hz, 1H). MS (ESI) m/e [M+1]⁺510.1.

The chiral separation conditions are shown below.

Column CHIRAL ART Cellulose-SB Column size 2 cm × 25 cm, 5 um Injection0.4 ML Mobile phase Hex:EtOH = 80:20 Flow rate 20 mL/min Wave length UV220 nm Temperature 25° C. Sample solution 21 mg/mL in EtOH:DCM = 3:1Prep-HPLC equipment Prep-Gilson-HPLC

Example 143-(1-(8-amino-1-methylimidazo[1,5-a]pyrazin-3-yl)ethyl)-5-chloro-6-fluoro-N-((1S,3R)-3-hydroxycyclopentyl)-2-isopropoxybenzamide(Compound 14)

The desired compound was prepared from compound 1-10 and(1R,3S)-3-aminocyclopentan-1-ol in a similar manner to compound 1-11 inExample 1. ¹H NMR (400 MHz, DMSO-d6) δ 8.70 (d, J=7.3 Hz, 1H) 7.41 (d,J==8.5 HZ, 1H), 7.31 (d, J=5.1 Hz, 1H), 6.91-6.74 (m, 3H), 4.79 (q,J=6.8 Hz, 1H), 4.61 (d, J=3.8 Hz, 1H), 4.51-4.41 (m, 1H), 4.17-4.03 (m,2H), 2.58 (s, 3H), 2.23-2.14 (m, 1H), 1.90-1.80 (m, 1H), 1.76-1.64 (m,1H), 1.64-1.49 (m, 5H), 1.42-1.32 (m, 1H), 1.19 (d, J=6.0 Hz, 3H), 1.07(d, J=6.0 Hz, 3H). MS (ESI) m/e [M+1]⁺ 490.1.

The compound 14 was separated by chiral column to give compound 14A(peak 1, S or R, retention time (RT) at 5.17 min in chiral analysis,Method I) and compound 14B (peak 2, R or S, retention time (RT) at 8.01min in chiral analysis, Method I).

Compound 14A: ¹H NMR (400 MHz, DMSO-d6) δ 8.70 (d, J=7.3 Hz, 1H), 7.41(d, J=8.5 Hz, 1H), 7.31 (d, J=5.1 Hz, 1H), 6.91-6.74 (m, 3H), 4.79 (q,J=6.8 Hz, 1H), 4.61 (d, J=3.8 Hz, 1H), 4.51-4.41 (m, 1H), 4.17-4.03 (m,2H), 2.58 (s, 3H), 2.23-2.14 (m, 1H), 1.90-1.80 (m, 1H), 1.76-1.64 (m,1H), 1.64-1.49 (m, 5H), 1.42-1.32 (m, 1H), 1.19 (d, J=6.0 HZ, 3H), 1.07(d, J=6.0 Hz, 3H). MS (ESI) m/e [M+1]⁺ 490.1.

Compound 14B: ¹H NMR (400 MHz, DMSO-d6) δ 8.69 (d, J=7.3 Hz, 1H), 7.39(d, J=8.5 Hz, 1H), 7.28 (d, J=5.1 Hz, 1H), 6.87 (d, J=5.0 Hz, 1H), 6.68(s, 2H), 4.78 (q, 1=6.8 Hz, 1H), 4.61 (d, J=3.8 Hz, 1H), 4.51-4.41 (m,1H), 4.17-4.03 (m, 2H), 2.57 (s, 3H), 2.23-2.14 (m, 1H), 1.90-1.80 (m,1H), 1.76-1.64 (m, 1H), 1.64-1.49 (m, 5H), 1.42-1.32 (m, 1H), 1.19 (d,J=6.0 Hz, 3H), 1.08 (d, J=6.0 Hz, 3H). MS (ESI) m/e [M+1]⁺ 490.1.

The chiral separation conditions are shown below.

Column CHIRAL ART Cellulose-SB Column size 2 cm × 25 cm, 5 um Injection0.4 ML Mobile phase Hex:EtOH = 80:20 Flow rate 20 mL/min Wave length UV220 nm Temperature 25° C. Sample solution 21 mg/mL in EtOH:DCM = 3:1Prep-HPLC equipment Prep-Gilson-HPLC

Example 15(S)-3-(1-(8-amino-1-methylimidazo[1,5-a]pyrazin-3-yl)ethyl)-5-chloro-N-(1-(ethoxymethyl)cyclopropyl)-6-fluoro-2-isopropoxybenzamide(Compound 15)

Step 1: 1-(5-chloro-4-fluoro-2-hydroxyphenyl)ethan-1-one (15-1)

To a 2 L three-necked flask equipped with a magnetic stirrer was added4-chloro-3-fluorophenol (160 g, 1.1 mol) and acetyl chloride (129 g, 1.6mmol). The mixture was stirred for 1 h. Then aluminum chloride (219 g,1.6 mmol) was added into the mixture in portions. The mixture was heatedto 160° C. and kept at 160° C. for 2 hrs. The mixture was cooled anddiluted with HCl (2 M, 500 mL). The resulting hot liquid was cooled andextracted with EtOAc (500 mL×3). The combined organic phase was washedwith water (500 mL), and brine (500 mL), dried over anhydrous sodiumsulfate, filtered and concentrated to give the product (200 g, crude) asa yellow solid, ¹H NMR (400 MHz, CDCl₃) δ 12.48-12.41 (m, 1H), 7.78 (d,J=8.1 Hz, 1H), 6.77 (d, J=10.3 Hz, 1H), 2.61 (s, 3H).

Step 2: 1-(3-bromo-5-chloro-4-fluoro-2-hydroxyphenyl)ethan-1-one (15-2)

To a solution of 1-(5-chloro-4-fluoro-2-hydroxyphenyl)ethan-1-one (110g, 583 mmol) in DMF (1 L) was added NBS (114 g, 640 mmol) in portions.The mixture was stirred at room temperature for 1 h. The mixture wasdiluted with water (3 L), extracted with EtOAc (1 L×3). The combinedorganic phase was washed with brine (1 L×3), dried over anhydrous sodiumsulfate, filtered and concentrated to give the product (150 g, crude) asa yellow solid. ¹H NMR (400 MHz, CDCl₃) δ 13.21 (d, J=1.8 Hz, 1H), 7.80(d, J=7.8 Hz, 1H), 2.66 (s, 3H).

Step 3: 1-(3-bromo-5-chloro-4-fluoro-2-isopropoxyphenyl)ethan-1-one(15-3)

To a solution of1-(3-bromo-5-chloro-4-fluoro-2-hydroxyphenyl)ethan-1-one (150 g, 560mmol) and 2-iodopropane. (143 g, 841 mmol) in DMF (1 L) was added NaHCO₃(71 g, 845 mmol). The mixture was stirred at 60° C. overnight. Themixture was cooled and diluted with water (3 L), extracted with EtOAc (1L×3). The combined organic phase was washed with brine (1 L×3), driedover anhydrous sodium sulfate, filtered and concentrated. The residuewas purified by silica gel column chromatography (elution withhexane/ethyl acetate=50/1) to give the product (140 g, 80%) as a yellowoil. ¹H NMR (400 MHz, CDCl3) δ 7.57 (d, J=8.2 Hz, 1H), 4.45-4.39 (m,1H), 2.61 (s, 3H), 1.31 (t, J=6.7 Hz, 6H).

Step 4: 2-(3-bromo-5-chloro-4-fluoro-2-isopropoxyphenyl)propanenitrile(15-4)

1-(3-bromo-5-chloro-4-fluoro-2-isopropoxyphenyl)ethan-1-one (165 g, 533mmol) in DME (420 mL) was added TOSMIC (156 g, 799 mmol), the solutionwas stirred at 0° C. a solution of t-BuOK (119.6 g, 1066 mmol) t-BuOH(840 mL) was added to the above solution by dropwise under N₂ andmaintained the temperature below 10° C., the resulting solution wasstirred at room temperature overnight. After completion, the reactionmixture was washed with water (1 L) and extracted with ethyl acetate(500 mL×3), dried over MgSO₄, filtered and evaporated in vacuo, Theresidue was purified by column chromatography (PE/EA=20:1˜10:1) to givethe product (118 g, 69.2%) as yellow solid. ¹H NMR (400 MHz, CDCl₃) δ7.51 (d, J=7.8 Hz, 1H), 4.69 (dt, J=12.3, 6.2 Hz, 1H), 4.31 (q, J=7.2Hz, 1H), 1.56 (d, J=7.2 Hz, 3H), 1.44 (d, J=6.2 Hz, 3H), 1.30 (d, J=6.2Hz, 3H).

Step 5: 2-(3-bromo-5-chloro-4-fluoro-2-isopropoxyphenyl)propanoic acid(15-5)

2-(3-bromo-5-chloro-4-fluoro-2-isopropoxyphenyl)propanenitrile (118 g,369 mmol) in EtOH (307 mL) was added a.q. NaOH (6 N, 307 mL), theresulting solution was stirred at 100° C. overnight. After completion,the reaction was cooled to room temperature, adjusted pH to 3˜4 byaddition of 1N HCl, extracted with ethyl acetate (500 mL×3), thecombined ethyl acetate phrase was dried over MgSO₄, filtered andevaporated to give the crude product (122 g, 97.4%) as yellow oil whichwas used in the next step without further purification. LC-MS(M−H)⁺=336.9.

Step 6: (S)-2-(3-bromo-5-chloro-4-fluoro-2-isopropoxyphenyl)propanoicacid (15-6)

2-(3-bromo-5-chloro-4-fluoro-2-isopropoxyphenyl)propanoic acid (122 g,359 mmol) and (1R,2S)-1-amino-2,3-dihydro-1H-inden-2-ol (54 g, 359 mmol)in i-PrOH (500 mL) was stirred at 100° C. for 1 h, cooled to r.t,concentrated to afford crude salt, which was slurried in PE/EA=10:1 (500mL) for 1˜2 h, undissolved solid was collected and refluxed in PE/EA/i-PrOH-20:2:1 (230 mL) for another 1 h, the solid was collected byfiltration and dried in vacuo to give the chiral salt which wasneutralized by addition of aq. (1N) to pH to 2˜3, extracted with ethylacetate (200 mL×3), dried over MgSO₄, concentrated to afford the productas yellow oil (44.2 g, 36.2%). ¹H NMR (400 MHz, DMSO-d6), δ 12.59 (s,1H), 7.52 (d, J=8.4 Hz, 1H), 4.55 (dt, J=12.3, 6.1 Hz, 1H), 4.04 (q,J=7.0, 1H), 1.38 (d, J=7.3 Hz, 3H), 1.34-1.26 (m, 6H). LC-MS(M−H)⁺=336.9. RetTime in chiral-HPLC: 2.61 min. The absolute (S)configuration of chiral center in compound 15-6 was confirmed by x-rayanalysis of single crystal.

Step 7:(2S)-2-(3-bromo-5-chloro-4-fluoro-2-isopropoxyphenyl)-N-(1-(3-chloropyrazin-2-yl)ethyl)propanamide(15-7)

(S)-2-(3-bromo-5-chloro-4-fluoro-2-isopropoxyphenyl)propanoic acid (52g, 153 mmol), 1-(3-chloropyrazin-2-yl)ethan-1-amine hydrochloride (29.7g, 153 mmol), EDCI (43.9 g, 229.7 mmol), HOBT (31 g, 229.7 mmol) andEt₃N (49.5 g, 489.6 mmol) in DCM (500 mL) was stirred at roomtemperature overnight under N₂. After completion the reaction solutionwas washed with H₂O (500 mL), extracted with DCM (500 mL×3), combinedDCM phase was dried over MgSO₄, concentrated and purified by columnchromatography (PE/EA=10:1˜5:1) to give the product (69 g, 94%) asyellow oil. LC-MS (M+H)⁺=479.6.

Step 8:(S)-3-(1-(3-bromo-5-chloro-4-fluoro-2-isopropoxyphenyl)ethyl)-8-chloro-1-methylimidazo[1,5-a]pyrazine(15-8)

(2S)-2-(3-bromo-5-chloro-4-fluoro-2-isopropoxyphenyl)-N-(1-(3-chloropyrazin-2-yl)ethyl)propanamide(69 g, 144 mmol) in DCM (1 L) was added Tf₂O (89.4 g, 317 mmol) bydropwise at 0° C., then pyridine (28.5 g, 360 mmol) was added bydropwise at 0° C., TLC showed the reaction was completed, H₂O (500 mL)was added, extracted with DCM (500 mL×3), combined DCM phase was driedover MgSO₄, concentrated to afford crude product which was slurried ini-PrOH (60 mL) for 1˜2 h, filtrated to give pure product as white solid(55 g, 83.4%). LC-MS (M+H)⁺=461.9.

Step 9:(S)-3-(1-(3-bromo-5-chloro-4-fluoro-2-isopropoxyphenyl)ethyl)-1-methylimidazo[1,5-a]pyrazin-8-amine(15-9)

To a pressure tank equipped with a magnetic stirrer were added(S)-3-(1-(3-bromo-5-chloro-4-fluoro-2-isopropoxyphenyl)ethyl)-8-chloro-1-methylimidazo[1,5-a]pyrazine(45 g, 97.6 mmol) and NH₃ in i-PrOH (w/w 30%, 300 mL, excess), Then themixture was stirred at 90° C. for two days. The mixture was cooled anddiluted with DCM (500 mL), washed with water (100 mL×3), brine (100 mL),dried over Na₂SO₄, filtered and concentrated to give the product (41 g,95%) as a yellow solid which was used in the next step without furtherpurification. ¹H NMR (400 MHz, CDCl₃) δ 7.27 (d, J=7.6 Hz, 1H), 7.15 (d,J=5.1 Hz, 1H), 6.88 (d, J=5.0 Hz, 1H), 4.78-4.69 (m, 2H), 2.72 (s, 3H),1.80 (d, J=7.2 Hz, 3H), 1.49 (d, J=6.2 Hz, 3H), 1.39 (d, J=6.2 Hz, 3H).LC-MS (M+H)⁺=441.0, 443.0.

Step 10:(S)-6-(1-(8-amino-1-methylimidazo[1,5-a]pyrazin-3-yl)ethyl)-2-bromo-4-chloro-3-fluorophenol(15-10)

To a mixture of(S)-3-(1-(3-bromo-5-chloro-4-fluoro-2-isopropoxyphenyl)ethyl)-1-methylimidazo[1,5-α]pyrazin-8-amine(41 g, 92.8 mmol) in DCM (500 mL) was added BBr₃ (70 g, 279 mmol) bydropwise at 0° C. Then the mixture was stirred at room temperatureovernight. The mixture was cooled to 0° C., and then quenched with MeOH(400 mL) carefully. The mixture was concentrated, the residue wasdiluted with a mixture of DCM (500 mL) and i-PrOH (100 mL). Then themixture was washed with saturated NaHCO₃ solution (100 mL×2). Theorganic layers were separated, washed with brine, dried over Na₂SO₄,filtered and concentrated to give the product (38 g, 100%) as a yellowsolid which was used for the next step without further purification. ¹HNMR (400 MHz, CDCl₃) δ 7.18 (d, J=5.2 Hz, 1H), 7.12 (d, J=7.9 Hz, 1H),7.02 (d, J=5.1 Hz, 1H), 4.28 (q, J=7.3 Hz, 1H), 4.08-398 (m, 1H), 2.72(s, 3H), 1.70 (d, J=7.3 Hz, 3H), 1.21 (d, J=6.1 Hz, 6H). LC-MS(M=H)⁺=399.0, 401.0.

Step 11: ethyl(S)-3-(1-(8-amino-1-methylimidazo[1,5-a]pyrazin-3-yl)ethyl)-5-chloro-6-fluoro-2-hydroxybenzoate(15-11)

To a mixture of(S)-6-(1-(8-amino-1-methylimidazo[1,5-a]pyrazin-3-yl)ethyl)-2-bromo-4-chloro-3-fluorophenol(38 g, 32.5 mmol) in EtOH (1000 mL) were added Pd(dppf)Cl₂ (3.5 g, 4.8mmol) and NaOAc (11.7 g, 143 mmol). The mixture was degassed andrefilled with CO (1 atm). The mixture was stirred at 70° C. overnight.The mixture was cooled down and concentrated in vacuo. The residue wasdiluted with water (200 mL), extracted with EtOAc (200 mL×3). Thecombined organic phase was washed with brine, dried over Na₂SO₄,filtered and concentrated. The residue was purified by columnchromatography (DCM/MeOH from DCM 100% to 20/1) to give the product (32g, 82%) as a yellow solid. ¹H NMR (400 MHz, CDCl₃) δ 7.28-7.24 (m, 1H),7.07 (d, J=5.1 Hz, 1H) 6.85 (d, J=5.1 Hz, 1H), 5.30 (s, 1H), 4.81 (q,J=7.1 Hz, 1H), 4.48 (q, 7.1 Hz, 2 Hz, 2.75 (s, 3H), 1.74 (d, J=7.1 Hz,3H), 1.43 (t, J=7.1 Hz, 3H). LC-MS (M+H)⁺=393.1.

Step 12: ethyl(S)-3-(1-(8-amino-1-methylimidazo[1,5-a]pyrazin-3-yl)ethyl-5-chloro-6-fluoro-2-isopropoxybenzoate(15-12)

ethyl(S)-3-(1-(8-amino-1-methylimidazo[1,5-a]pyrazin-3-yl)ethyl)-5-chloro-6-fluoro-2-hydroxybenzoate(32 g, 81.5 mmol), i-PrOH (24.4 g, 406.7 mmol), PPh₃ (49.1 g, 187.5mmol) in toluene (400 mL) was added di-tert-butyl(E)-diazene-1,2-dicarboxylate (43.2 g, 187.5 mmol) at room temperature.The resulting solution was stirred at 60° C. for 3 hrs under N₂. Aftercompletion, the reaction mixture was concentrated in vacuo, washed withH₂O (500 mL), extracted with EtOAc (500 mL×3), combined EtOAc phase wasdried over MgSO₄, purified by column chromatography (PE/EA=20:1) to givethe product (25.4 g, 71.8%) as yellow solid. LC-MS (M+H)⁺=435.1.

Step 13:(S)-3-(1-(8-amino-1-methylimidazo[1,5-a]pyrazin-3-yl)ethyl)-5-chloro-6-fluoro-2-isopropoxybenzoicacid (15-13)

ethyl(S)-3-(1-(8-amino-1-methylimidazo[1,5-a]pyrazin-3-yl)ethyl)-5-chloro-6-fluoro-2-isopropoxybenzoate(25.4 g, 58.5 mmol) in MeOH (100 mL) and H₂O (100 mL) was added NaOH(18.7 g, 468 mmol), the resulting solution was stirred at roomtemperature overnight. After completion, the reaction solution wasconcentrated in vacuo to remove most of the MeOH, remaining solution wasextracted with EtOAc (100 mL×2), the aqueous phase was adjusted pH to2˜3, blown solid was precipitated, collected by filtration, dried invacuo to give the product (15.8 g), the aqueous phase was extracted withDCM (1.00 mL×5) combined DCM phase was dried over MgSO₄ and concentratedin vacuo to give another part of product (2.2 g), total yield (18 g,75.6%). ¹H NMR (400 MHz, DMSO-d6) δ 7.78 (brs, 2H), 7.40-7.32 (m, 2H),6.93 (d, J=5.3 HZ, 1H), 4.80 (q, J 7.0 Hz, 1H), 4.55 (dt, J=12.1, 6.0Hz, 1H), 2.60 (s, 3H), 1.60 (d, J=7.0 Hz, 3H), 1.20 (d, J=6.0 Hz, 3H),1.13 (d, J=6.0 Hz, 3H). LC-MS (M+H)⁺=407.1.

Step 14:(S)-3-(1-(8-amino-1-methylimidazo[1,5-α]pyrazin-3-yl)ethyl)-5-chloro-N-(1-(ethoxymethyl)cyclopropyl)-6-fluoro-2-isopropoxybenzamide(15-14)

To a solution of(S)-3-(1-(8-amino-1-methylimidazo[1,5-a]pyrazin-3-yl)ethyl)-5-chloro-6-fluoro-2-isopropoxybenzoicacid (100 mg, 0.25 mmol) and 1-(ethoxymethyl)cyclopropan-1-aminehydrochloride (60 mg, 0.4 mmol) in DMF (10 mL) were added Et₃N (125 mg,1.25 mmol) and PyBop (210 mg, 0.4 mmol). The mixture was stirred at roomtemperature for 1 h. The mixture was diluted with water (30 mL),extracted with EtOAc (30 mL×3). The combined organic layers were washedwith water (50 mL×2) and brine (50 mL), dried over Na₂SO₄, filtered andevaporated. The residue was purified by thin layer chromatography(DCM/MeOH=15/1) to give the product (90 mg, 71%). ¹H NMR (400 MHz,DMSO-d6) δ 8.98 (brs, 1H), 7.36 (d, J=8.9 Hz, 1H), 7.24 (brs, 1H), 6.86(brs, 1H), 6.44 (brs, 2H), 4.77 (brs, 1H), 4.51 (brs, 1H), 3.56-3.41 (m,4H), 2.57 (s, 3H), 1.58 (brs, 3H), 1.19 (brs, 3H), 1.09 (brs, 6H), 0.77(brs, 2H), 0.70 (brs, 2H). LC-MS (M+H)⁺=504.2. RetTime in chiral-HPLC:2.75 min, Method. J.

Example 16

(S)-3-(1-(8-amino-1-methylimidazo[1,5-a]pyrazin-3-yl)ethyl)-5-chloro-N-(2-(dimethylamino)ethyl)-6-fluoro-2-isopropoxybenzamide(Compound 16)

This compound (50.3 mg, 21.4%) was prepared from compound 15-13 andN¹,N¹-dimethylethane-1,2-diamine in a similar manner to compound 15-14in Example 15. ¹H NMR (400 MHz, DMSO-d6) δ 8.66 (t, J=5.5 Hz, 1H), 7.38(d, J=8.6 Hz, 1H), 7.25 (d, J=5.0 Hz, 1H), 6.85 (d, J=5.0 Hz, 1H), 6.43(s, 2H), 4.77 (q, J=7.0 Hz, 1H), 4.52 (dt, J=12.2, 6.1 Hz, 1H),3.35-3.25 (m, 2H), 2.56 (s, 3H), 2.37 (s, 2H), 2.17 (s, 6H), 1.58 (d,J=7.1 Hz, 3H), 1.18 (d, J=6.0 Hz, 3H), 1.08 (d, J=6.0 Hz, 3H). LC-MS(M+H)⁺=477.2. RetTime in chiral-HPLC: 4.34 min, Method A.

Example 17(3-((S)-1-(8-amino-1-methylimidazo[1,5-a]pyrazin-3-yl)ethyl)-5-chloro-6-fluoro-2-isopropoxyphenyl)((S)-2-(methoxymethyl)pyrrolidin-1-yl)methanone(Compound 17)

This compound (26.4 mg, 10.6%) was prepared from compound 15-13 and(S)-2-(methoxymethyl)pyrrolidine in a similar manner to compound 15-14in Example 15. ¹H NMR (400 MHz, DMSO-d6) δ 7.43-7.29 (m, 1H), 7.27-7.16(m, 1H), 6.90-6.75 (m, 1H), 6.56-6.34 (m, 2H), 4.76 (dd, J=13.8, 7.0 Hz,1H), 4.39 (ddd, J=24.1, 12.2, 6.0 Hz, 1H), 3.73-3.41 (m, 3H), 3.33-3.27(m, 3H), 3.22-3.10 (m, 1H), 3.00-2.80 (m, 1H), 2.62-2.54 (m, 3H),2.02-1.72 (m, 4H), 1.70-1.63 (m, 3H), 1.30-1.15 (m, 6H). LC-MS(M+H)⁺=504.2 RetTime in chiral-HPLC: 4.36 min and 4.82 min, Method C.

Example 18(S)-3-(1-(8-amino-1-methylimidazo[1,5-a]pyrazin-3-yl)ethyl)-5-chloro-6-fluoro-N-(4-fluorophenyl)-2-isopropoxybenzamide(Compound 18)

This compound (8 mg, 6.5%) was prepared from compound 15-13 and4-fluoroaniline in a similar manner to compound 15-14 in Example 15. ¹HNMR (400 MHz, DMSO-d6) δ 10.79 (s, 1H), 7.75-7.62 (m, 2H), 7.57-7.30 (m,2H), 7.28-7.05 (m, 3H), 6.92-6.68 (m, 2H), 4.89-4.75 (m, 1H), 4.48-4.36(m, 1H), 2.60-2.54 (m, 3H), 1.69-1.51 (m, 3H), 1.20-1.11 (m, 3H),1.07-0.98 (m, 3H). LC-MS (M+H)⁺=500.1 RetTime in chiral-HPLC: 4.10 min,Method C.

Example 19(5)-(3-(1-(8-amino-1-methylimidazo[1,5-a]pyrazin-3-yl)ethyl)-5-chloro-6-fluoro-2-isopropoxyphenyl)(4-methoxypiperidin-1-yl)methanone(Compound 19)

This compound (36.4 mg, 14.6%) was prepared from compound 15-13 and4-methoxypiperidine in a similar manner to compound 15-14 in Example 15.¹H NMR (400 DMSO-d6) δ 7.47-7.13 (m, 2H), 6.89-6.75 (m, 1H), 6.74-6.47(m, 2H), 4.86-4.67 (m, 1H), 4.48-4.23 (m, 1H), 4.19-3.71 (m, 1H),3.60-3.36 (m, 2H), 3.29-3.23 (m, 3H), 3.21-2.89 (m, 2H), 2.62-2.55 (m,3H), 2.01-1.29 (m, 7H), 1.29-0.94 (m, 6H). LC-MS (M+H)⁺=504.2. RetTimein chiral-HPLC: 4.35 min, Method C.

Example 20(3-((S)-1-(8-amino-1-methylimidazo[1,5-a]pyrazin-3-yl)ethyl)-5-chloro-6-fluoro-2-isopropoxyphenyl)((S)-3-hydroxypiperidin-1-yl)methanone(Compound 20)

This compound (31 g, 12.8%) was prepared from compound 15-13 and(S)-piperidin-3-ol in a similar manner to compound 15-14 in Example 15.¹H NMR (400 MHz, DMSO-d6) δ 7.46-7.10 (m, 2H), 6.90-6.76 (m, 1H),6.72-6.42 (m, 2H), 5.15-4.65 (m, 2H), 4.51-4.26 (m, 1H), 3.24-2.90 (m,2H), 2.89-2.64 (m, 2H), 2.61-2.55 (m, 3H), 2.01-1.71 (m, 1H), 1.71-1.61(m, 3H), 1.59-1.53 (m, 1H), 1.42-1.31 (m, 2H), 1.30-1.12 (m, 6H). LC-MS(M+H)⁺=490.2. RetTime in chiral-HPLC: 5.68 min, Method C.

Example 213-((S)-1-(8-amino-1-methylimidazo[1,5-a]pyrazin-3-yl)ethyl)-5-chloro-6-fluoro-2-isopropoxy-N—((S)-1-phenylethyl)benzamide(Compound 21)

This compound (46 mg, 36.5%) was prepared from compound 15-13 and(S)-1-phenylethan-1-amine in a similar manner to compound 15-14 inExample 15. ¹H NMR (400 MHz, DMSO-d6) δ 9.21 (d, J=8.1 Hz, 1H), 7.46 (d,J=8.5 Hz, 1H), 7.42-7.30 (m, 5H), 7.28-7.17 (m, 2H), 6.91 (d, J=5.2 Hz,1H), 5.10 (p, J=7.0 Hz, 1H), 4.79 (q, J=6.8 Hz, 1H), 4.27 (dt, J=12.0,6.0 Hz, 1H), 2.58 (s, 3H), 1.57 (d, J=7.0 Hz, 3H), 1.40 (d, J=7.0 Hz,3H), 1.03 (d, J=6.0 Hz, 3H), 0.86 (d, J=5.9 Hz, 3H). LC-MS (M=H)⁺=509.8.RetTime in chiral-HPLC: 2.67 min., Method F.

Example 223-((S)-1-(8-amino-1-methylimidazo[1,5-a]pyrazin-3-yl)ethyl)-5-chloro-6-fluoro-2-isopropoxy-N—((R)-1-phenylethyl)benzamide(Compound 22)

This compound (26 mg, 20.7%) was prepared from compound 15-13 and(R)-1-phenylethan-1-amine in a similar manner to compound 15-14 inExample 15. ¹H NMR (400 MHz, DMSO-d6) δ 9.21 (d, J=8.1 Hz, 1H), 7.47 (d,J=8.6 Hz, 1H), 7.41-7.31 (m, 5H), 7.30-7.09 (m, 2H), 6.90 (d, J=5.3 Hz,1H), 5.09 (p, J=7.0 Hz, 1H), 4.79 (q, J=6.9 Hz, 1H), 4.28-4.16 (m, 1H),2.58 (s, 3H), 1.56 (d, J=7.0 Hz, 3H), 1.40 (d, J=7.0 Hz, 3H), 1.01 (d,J=6.0 Hz, 3H), 0.87 (d, J=6.0 HZ, 3H). LC-MS (M+H)⁺509.8. RetTimechiral-HPLC: 5.35 min, Method A

Example 233-((S)-1-(8-amino-1-methylimidazo[1,5-a]pyrazin-3-yl)ethyl)-5-chloro-6-fluoro-N-((1R,2S)-2-hydroxycyclopentyl)-2-isopropoxybenzamide(Compound 23)

This compound (1.4.1 mg, 11.7%) was prepared from compound 15-13 and(1S,2R)-2-aminocyclopentan-1-ol in a similar manner to compound 15-14 inExample 15, ¹H NMR (400 MHz, DMSO-d6) δ 8.29 (d, J=7.4 Hz, 1H), 7.35 (d,J=8.6 Hz, H), 7.24 (d, J=5.1 Hz, 1H), 6.85 (d, J=5.0 Hz, 1H), 6.53 (s,2H), 4.77 (q, J=7.4 Hz, 1H), 4.61-4.47 (m, 2H), 4.08-3.94 (m, 2H), 2.57(s, 3H), 1.92-1.67 (m, 3H), 1.65-1.44 (m, 6H), 1.19 (d, J=6.0 Hz, 3H),1.11 (d, J=6.0 Hz, 3H). LC-MS (M+H)⁺=489.8. RetTime its chiral-HPLC:4.63 min, Method A.

Example 243-((S)-1-(8-amino-1-methylimidazo[1,5-a]pyrazin-3-yl)ethyl)-5-chloro-6-fluoro-2-isopropoxy-N—(((S)-tetrahydrofuran-2-yl)methyl)benzamide(Compound 24)

This compound (20.63 mg, 17.1%) was prepared from compound 15-13 and(S)-(tetrahydrofuran-2-yl)methanamine in a similar manner to compound15-14 in Example 15. ¹H NMR (400 MHz, DMSO-d6) δ 8.78 (t, J=5.8 Hz, 1H),7.41 (d, J=8.6 Hz, 1H), 7.32 (d, J=5.3 Hz, 1H), 6.90 (s, 2H), 6.88 (d,J=5.2 Hz, 1H), 4.79 (q, J=7.0 Hz, 1H), 4.49 (dt, J=12.1, 6.0 Hz, 1H),3.92 (p, J=6.3 Hz, 1H), 3.75 (dd, J=14.0, 7.2 Hz, 1H), 3.61 (dd, J=14.5,7.3 Hz, 1H), 3.31-3.26 (m, 2H), 2.58 (s, 3H), 1.96-1.74 (m, 3H),1.64-1.50 (m, 4H), 1.18 (d, J=6.0 Hz, 3H), 1.08 (d, J=6.1 Hz, 3H). LC-MS(M=H)⁺=489.8. RetTime in chiral-HPLC: 5.52 min, Method A.

Example 253-((S)-1-(8-amino-1-methylimidazo[1,5-a]pyrazin-3-yl)ethyl)-5-chloro-6-fluoro-N-((1S,2R)-2-hydroxycyclopentyl)-2-isopropoxybenzamide(Compound 25)

This compound (23.32 mg, 19.3%) was prepared from compound 15-13 and(1R,2S)-2-aminocyclopentan-1-ol in a similar manner to compound 15-14 inExample 15. ¹H NMR (400 MHz, DMSO-d6) δ 8.34 (d, J=7.1 Hz, 1H), 7.57 (s,2H), 7.46-7.38 (m, 2H), 6.93 (d, J=5.4 Hz, 1H), 4.82 (q, J=6.8 Hz, 1H),4.60 (d, J=2.7 Hz, 1H), 4.52 (dt, J=11.9, 5.9 Hz, 1H), 4.01 (brs, 2H),2.60 (s, 3H), 1.90-1.65 (m, 3H), 1.64-1.43 (m, 6H), 1.18 (d, J=6.1 Hz,3H), 1.04 (d, J=5.9 Hz, 3H). LC-MS (M+H)⁺=489.8. RetTime in chiral-HPLC:4.68 min, Method A

Example 26(S)-3-(1-(8-amino-1-methylimidazo[1,5-a]pyrazin-3-yl)ethyl)-5-chloro-6-fluoro-2-isopropoxy-N-(2-(tetrahydro-2H-pyran-4-yl)ethyl)benzamide(Compound 26)

This compound (15 mg, 11.8%) was prepared from compound 15-13 and2-tetrahydro-2H-pyran-4-yl)ethan-1-amine in a similar manner to compound15-14 in Example 15. ¹H NMR (400 DMSO-d6) δ 8.66 (t, J=5.5 Hz, 1H), 7.41(d, J=8.6 Hz, 1H), 7.29 (d, J=5.1 Hz, 1H), 6.87 (d, J=4.9 Hz, 1H), 6.65(s, 2H), 4.78 (q, J=7.0 Hz, 1H), 4.45 (dt, J=12.1, 5.9 HZ, 1H),3.93-3.74 (m, 2H), 3.34-3.15 (m, 3H), 2.57 (s, 3H), 1.65-1.50 (m, 6H),1.47-1.37 (m, 2H), 1.27-1.12 (m, 5H), 1.08 (d, J=6.0 Hz, 3H). LC-MS(M+H)⁺=517.8. RetTime in chiral-HPLC: 6.39 min, Method A

Example 27(S)-3-(1-(8-amino-1-methylimidazo[1,5-a]pyrazin-3-yl)ethyl)-5-chloro-6-fluoro-2-isopropoxy-N-methylbenzamide(Compound 27)

This compound (11 mg, 10.6%) was prepared from compound 15-13 andmethenamine in a manner similar to similar manner to compound 15-14 inExample 15. ¹H NMR (400 MHz, DMSO-d6) δ 8.60 (t, J=4.7 Hz, 1H), 7.40 (d,J=8.6 Hz, 1H), 7.26 (d, J=5.1 Hz, 1H), 6.87 (d, J=5.0 Hz, 1H), 6.58 (s,2H), 4.77 (q, J=7.0 Hz, 1H), 4.39 (dt, J=12.1, 6.0 Hz, 1H), 2.75 (d,J=4.6 Hz, 3H), 2.57 (s, 3H), 1.58 (d, J=7.1 Hz, 3H), 1.19 (d, J=6.1 Hz,3H), 1.09 (d, J=6.1 Hz, 3H). LC-MS (M+H)⁺=419.8. RetTime in chiral-HPLC:4.44 min, Method A

Example 28(S)-3-(1-(8-amino-1-methylimidazo[1,5-a]pyrazin-3-yl)ethyl)-5-chloro-6-fluoro-2-isopropoxy-N-ethyl-benzamide(Compound 28)

This compound (36.1 mg, 33.8%) was prepared from compound 15-13 andethanamine in a similar manner to compound 15-14 in Example 15. ¹H NMR(400 MHz, DMSO-d6) δ 8.68 (t, J=5.3 Hz, 1H), 7.41 (d, J=8.6 Hz, 1H),7.28 (d, J=5.1 Hz, 1H), 6.87 (d, J=5.1 Hz, 1H), 6.60 (s, 2H), 4.78 (q,J=7.1 Hz, 1H), 4.45 (dt, J=12.1, 6.0 Hz, 1H), 3.28-3.18 (m, 2H), 2.57(s, 3H), 1.58 (d, J=7.1 Hz, 3H), 1.19 (d, J=6.0 Hz, 3H), 1.13-1.04 (m,6). LC-MS (M+H)⁺=433.8. RetTime in chiral-HPLC: 5.12 min, Method A

Example 29(S)-3-(1-(8-amino-1-methylimidazo[1,5-a]pyrazin-3-yl)ethyl)-5-chloro-6-fluoro-2-isopropoxy-N-(4-methoxyphenyl)benzamide(Compound 29)

This compound (35 mg, 18.2%) was prepared from compound 15-13 and4-methoxyaniline in a similar manner to compound 15-14 in Example 15. ¹HNMR (400 MHz, DMSO-d6) δ 10.60 (s, 1H), 7.60-7.50 (m, J==8.7, 4.2 Hz,3H), 7.43 (d, J=5.4 HZ, 1H), 7.39 (s, 2H), 6.98-6.87 (m, 3H), 4.85 (q,J=6.9 Hz, 1H), 4.45 (dt, J=12.1, 6.2 Hz, 1H), 3.74 (s, 3H), 2.60 (s,3H), 1.61 (d, J=7.1 Hz, 3H), 1.18 (d, J=6.1 Hz, 3H), 1.04 (d, J=6.1 Hz,3H). LC-MS (M+H)⁺=511.8. RetTime in chiral-HPLC: 3.97 min, Method B

Example 30(S)-3-(1-(8-amino-1-methylimidazo[1,5-a]pyrazin-3-yl)ethyl)-5-chloro-6-fluoro-2-isopropoxy-N-((1-methylpiperidin-4-yl)methyl)benzamide(Compound 30)

This compound (1.3 mg, 10.2%) was prepared from compound 15-13 and(1-methylpiperidin-4-yl)methanamine in a similar manner to compound15-14 in Example 15. ¹H NMR (400 MHz, DMSO-d6) δ 10.50 (brs, 1H), 8.84(t, J=5.8 Hz, 1H), 7.63 (brs, 1H), 7.50 (d, J=8.5 Hz, 1H), 7.44 (d,J=5.5 Hz, 1H), 6.96 (d, J=5.4 Hz, 1H), 4.82 (q, J=6.9 Hz, 1H), 4.43 (dt,J=11.8, 6.0 Hz, 1H), 3.43-3.34 (m, 2H), 3.18-3.05 (m, 2H), 2.96-2.82 (m,2H), 2.68 (s, 3H), 2.59 (s, 3H), 1.84 (d, J=13.3 Hz, 2H), 1.78-1.65 (m,1H), 1.59 (d, J=7.0 Hz, 3H), 1.54-1.39 (m, 2H), 1.18 (d, J=6.0 Hz, 3H),1.07 (d, J=6.0 Hz, 3H). LC-MS (M+H)⁺=516.8. RetTime in chiral-HPLC: 2.78min, Method B

Example 313-((S)-1-(8-amino-1-methylimidazo[1,5-a]pyrazin-3-yl)ethyl)-5-chloro-6-fluoro-2-isopropoxy-N—(((R)-tetrahydrofuran-2-yl)methyl)benzamide(Compound 31)

This compound (8 mg, 6.6%) was prepared from compound 15-13 and(R)-(tetrahydrofuran-2-yl)methanamine in a similar manner to compound15-14 in Example 15. ¹H NMR (400 MHz, DMSO-d6) δ 8.78 (t, J=5.7 Hz, 1H),7.40 (d, J=8.6 Hz, 1H), 7.28 (d, J=5.1 Hz, 1H), 6.87 (d, J=5.1 Hz, 1H),6.65 (s, 2H), 4.78 (q, J=6.9 Hz, 1H), 4.48 (dt, J=12.2, 6.1 Hz, 1H),3.92 (dt, J=12.0, 6.4 Hz, 1H), 3.75 (dd, J=14.2, 7.0 Hz, 1H), 3.61 (dd,J=14.4, 7.3 Hz, 1H), 3.35-3.22 (m, 2H), 2.57 (s, 3H), 1.97-1.73 (m, 3H),1.63-1.51 (m, 4H), 1.18 (d, J=6.1 Hz, 3H), 1.08 (d, J=6.0 Hz, 3H). LC-MS(M+H)⁺=489.8. RetTime in chiral-HPLC: 3.49 min, Method B

Example 32(S)-3-(1-(8-amino-1-methylimidazo[1,5-a]pyrazin-3-yl)ethyl)-5-chloro-6-fluoro-2-isopropoxy-N,N-dimethylbenzamide(Compound 32)

This compound (26 mg, 24.4%) was prepared from compound 15-13 anddimethylamine in a similar manner to compound 15-14 in Example 15. ¹HNMR (400 MHz, DMSO-d6) δ 7.53-6.97 (m, 4H), 6.94-6.79 (m, 1H), 4.86-4.73(m, 1H), 4.42-4.15 (m, 1H), 3.08-2.97 (m, 3H), 2.91-2.71 (m, 3H), 2.59(s, 3H), 1.75-1.51 (m, 3H), 1.30-0.92 (m, 6H). LC-MS (M+H)⁺=433.8,RetTime in chiral-HPLC: 4.05 min and 4.01 min, Method B

Example 33(S)-3-(1-(8-amino-1-methylimidazo[1,5-a]pyrazin-3-yl)ethyl)-5-chloro-6-fluoro-2-isopropoxy-N-(pyridin-2-ylmethyl)benzamide(Compound 33)

This compound (103 mg 83.1%) was prepared from compound 15-13 andpyridin-2-ylmethanamine in a similar manner to compound 15-14 in Example15. ¹H NMR (400 MHz, DMSO-d6) δ 9.33 (brs, 1H), 8.51 (brs, 1H),7.83-7.79 (m, 1H), 7.48-7.45 (m, 1H), 7.40-7.34 (m, 2H), 7.30-7.28 (m,1H), 7.18 (brs, 2H), 6.91-6.90 (m, 1H), 4.81-4.79 (m, 1H), 4.52 (brs,2H), 4.42-4.40 (m, 1H), 2.59-2.58 (m, 3H), 1.60-1.58 (m, 3H), 1.12-1.10(m, 3H), 0.99-0.98 (m, 3H), LC-MS (M+H)+=497.2. RetTime in chiral-HPLC:2.83 min, Method E.

Example 343-((S)-1-(8-amino-1-methylimidazo[1,5-a]pyrazin-3-yl)ethyl)-5-chloro-6-fluoro-2-isopropoxy-N—(((R)-tetrahydrofuran-3-yl)methyl)benzamide(Compound 34)

This compound (93.8 mg, 81.7%) was prepared from compound 15-13 and(R)-(tetrahydrofuran-3-yl)methanamine in a similar manner to compound15-14 in Example 15. ¹H NMR (400 MHz, DMSO-d6) δ 8.83 (brs, 1H),7.47-7.45 (m, 1H), 7.38-7.37 (m, 1H), 7.18-7.07 (brs, 2H), 6.91-6.90 (m,1H), 4.81-4.77 (m, 1H), 4.44-4.41 (m, 1H), 3.75-3.59 (m, 3H), 3.43-3.40(m, 1H), 3.21-3.17 (m, 2H), 2.58 (brs, 3H), 2.44-2.40 (m, 2H), 1.95-1.91(m, 1H), 1.59-1.58 (m, 3H), 1.07-1.06 (m, 3H). LC-MS (M+H)+=490.2.RetTime in chiral-HPLC: 2.59 min, Method E

Example 353-((S)-1-(8-amino-1-methylimidazo[1,5-a]pyrazin-3-yl)ethyl)-5-chloro-6-fluoro-2-isopropoxy-N—(((S)-tetrahydrofuran-3-yl)methyl)benzamide(Compound 35)

This compound (93.0 mg, 78.2%) was prepared from compound 15-13 and(S)-(tetrahydrofuran-3-yl)methanamine in a similar manner to compound15-14 in Example 15. ¹H NMR (400 MHz, DMSO-d6) δ 8.83-8.80 (t, 1H),7.45-7.43 (d, J=8.4 Hz, 1H), 7.33-7.32 (d, J=5.2 Hz, 1H), 6.89-6.87 (d,J=5.2 Hz, 1H), 6.83 (brs, 2H), 4.82-4.76 (m, 1H), 4.47-4.41 (m, 1H),3.75-3.59 (m, 3H), 3.45-3.40 (m, 1H), 3.27-3.14 (m, 2H), 2.57 (s, 3H),2.47-2.37 (m, 2H), 1.98-1.89 (m, 1H), 1.62-1.53 (m, 4H), 1.19-1.17 (d,J=6.4 Hz, 3H), 1.08-1.07 (d, J=6.0 Hz, 3H). LC-MS (M+H)+=490.1. RetTimein chiral-HPLC: 3.56 min, Method F

Example 363-((S)-1-(8-amino-1-methylimidazo[1,5-a]pyrazin-3-yl)ethyl)-5-chloro-6-fluoro-2-isopropoxy-N—((R)-1-(4-methoxyphenyl)ethyl)benzamide(Compound 36)

This compound (98.3 mg, 82.1%) was prepared from compound 15-13 and(R)-1-(4-methoxyphenyl)ethan-1-amine in a similar manner to compound15-14 in Example 15.

¹H NMR (400 MHz, DMSO-d6) δ 9.14-9.12 (d, J=8.0 Hz, 1H), 7.45-7.43 (d,J=8.4 Hz, 1H), 7.35-7.34 (d, J=5.2 Hz, 1H), 7.39-7.26 (d, J=8.4 Hz, 2H),7.05 (brs, 2H), 6.91-6.89 (m, 3H), 5.07-5.03 (m, 1H), 4.80-4.75 (m, 1H),4.25-4.21 (m, 1H), 3.73 (s, 3H), 2.57 (s, 3H), 1.57-1.55 (d, J=7.2 Hz,3H), 1.39-1.37 (d, J=6.8 Hz, 3H), 1.01-1.03 (d, J=6.0 Hz, 3H), 0.89-0.90(d, J=6.0 Hz, 3H). LC-MS (M+H)+=539.8. RetTime in chiral-HPLC: 8.996min, Method G.

Example 373-((S)-1-(8-amino-1-methylimidazo[1,5-a]pyrazin-3-yl)ethyl)-5-chloro-6-fluoro-2-isopropoxy-N-((1S,2S)-2-hydroxycyclopentyl)benzamide(Compound 37)

This compound (78.0 mg, 74.7%) was prepared from compound 15-13 and(1S,2S)-2-aminocyclopentan-1-ol in a similar manner to compound 15-14 inExample 15. ¹H NMR (400 MHz, DMSO-d6) δ 8.60-8.58 (d, J=8.0 Hz, 1H),7.43-7.41 (d, J=8.8 Hz, 1H), 7.33-7.32 (d, J=5.2 Hz, 1H), 6.89-6.88 (m,3H), 4.80-4.75 (m, 2H), 4.52-4.48 (m, 1H), 3.95-3.90 (m, 2H), 2.57 (s,3H), 1.99-1.96 (m, 1H), 1.78-1.74 (m, 1H), 1.66-1.61 (m, 2H), 1.58-1.56(d, J=7.2 Hz, 3H), 1.48-1.36 (m, 3H), 1.18-1.16 (d, J=6.4 Hz, 3H),1.06-1.05 (d, J=5.6 Hz, 3H). LC-MS (M+H)+=489.8. RetTime in chiral-HPLC:3.012 min, Method F

Example 383-((S)-1-(8-amino-1-methylimidazo[1,5-a]pyrazin-3-yl)ethyl)-5-chloro-6-fluoro-2-isopropoxy-N-((1S,3R)-3-hydroxy-1-methylcyclobutyl)benzamide(Compound 38)

This compound (58.3 mg, 52.9%) was prepared from compound 15-13 and(1S,3S)-3-amino-3-methylcyclobutan-1-ol in a similar manner to compound15-14 in Example 15. ¹H NMR (400 MHz, DMSO-d6) δ 8.84 (s, 1H), 7.43-7.41(d, J=8.8 Hz, 1H), 7.36-7.34 (d, J=5.6 Hz, 1H), 7.06 (brs, 1H),6.91-6.90 (d, J=5.2 Hz, 1H), 5.08-5.06 (d, J=6.4 Hz, 1H), 4.82-4.77 (m,1H), 4.58-4.52 (m, 1H), 4.03-3.97 (m, 1H), 2.58 (s, 3H), 2.39-2.34 (m,2H), 2.05-2.00 (m, 2H), 1.59-1.57 (d, J=6.8 Hz, 3H), 1.36 (s, 3H),1.21-1.19 (d, J=6.0 Hz, 3H), 1.10-1.09 (d, J=6.0 Hz, 3H). LC-MS(M+H)+=489.8. RetTime in chiral-HPLC: 5.309 min, Method A

Example 393-((S)-1-(8-amino-1-methylimidazo[1,5-a]pyrazin-3-yl)ethyl)-5-chloro-6-fluoro-N-((1r,3S)-3-hydroxy-1-methylcyclobutyl)-2-isopropoxybenzamide(Compound 39)

This compound (61.2 mg, 56.3%) was prepared from compound 15-13 and(1R,3R)-3-amino-3-methylcyclobutan-1-ol in a similar manner to compound15-14 in Example 15. ¹H NMR (400 MHz, DMSO-d6) δ 8.70 (s, 1H), 7.43-7.41(d, J=8.8 Hz, 1H), 7.36-7.34 (d, J=5.2 Hz, 1H), 7.02 (brs, 1H),6.91-6.90 (d, J=5.2 Hz, 1H), 5.06-5.05 (d, J=5.6 Hz, 1H), 4.82-4.77 (m,1H), 4.56-4.49 (m, 1H), 4.12-4.07 (m, 1H), 2.63-2.60 (m, 2H), 2.58 (s,3H), 1.82-1.77 (m, 2H), 1.58-1.57 (d, J=6.8 Hz, 3H), 1.43 (s, 3H),1.20-1.18 (d, J=6.4 Hz, 3H), 1.08-1.07 (d, J=6.0 Hz, 3H). LC-MS(M+H)+=489.8. RetTime in chiral-HPLC: 5.500 min, Method A

Example 403-((S)-4-(8-amino-1-methylimidazo[1,5-a]pyrazin-3-yl)ethyl)-5-chloro-6-fluoro-N-((1R,4S)-4-hydroxy-1-methylcyclohexyl)-2-isopropoxybenzamide(Compound 40)

This compound (61.2 mg, 54.1%) was prepared from compound 15-13 and(1R,4R)-4-amino-4-methylcyclohexan-1-ol in a similar manner to compound15-14 in Example 15. ¹H NMR (400 MHz, DMSO-d6) δ 8.11 (s, 1H), 7.42-7.37(m, 2H), 7.13 (brs, 1H), 6.92-6.91 (d, J=5.2 Hz, 1H), 4.83-4.78 (m, 1H),4.63-4.56 (m, 1H), 4.53-4.52 (m, 1H), 3.45-3.42 (m, 2H), 2.58 (s, 3H),2.24-2.16 (m, 2H), 1.59-1.54 (m, 5H), 1.42-1.38 (m, 2H), 1.30 (s, 3H),1.27-1.23 (m, 2H), 1.20-1.18 (d, J=5.6 Hz, 3H), 1.09-1.07 (d, J=6.0 Hz,3H). LC-MS (M+H)⁺=417.8. Ref rime in chiral-HPLC: 5.609 min, Method A.

Example 41(S)-3-(1-(8-amino-1-methylimidazo[1,5-a]pyrazin-3-yl)ethyl-5-chloro-6-fluoro-2-isopropoxy-N-propylbenzamide(Compound 41)

This compound (63 mg, 57.3%) was prepared from compound 15-13 andpropan-1-amine in a similar manner to compound 15-14 in Example 15. ¹HNMR (400 MHz, DMSO d6) δ 8.66 (s, 1H), 7.41 (d, J=4.8 Hz, 1H), 7.31(brs, 1H), 6.86 (brs, 3H), 4.77 (brs, 1H), 4.44 (brs, 1H), 3.21-3.10 (m,2H), 2.56 (s, 3H), 1.57 (brs, 3H), 1.48 (brs, 2H), 1.17 (brs, 3H), 1.06(brs, 3H), 0.87 (brs, 3H). LC-MS (M+H)⁺=448.2. RetTime in chiral-HPLC:3.43 min, Method C

Example 42(S)-3-(1-(8-amino-1-methylimidazo[1,5-a]pyrazin-3-yl)ethyl)-5-chloro-N-(cyclopropylmethyl)-6-fluoro-2-isopropoxybenzamide(Compound 42)

This compound (73 mg, 64.3%) was prepared from compound 15-13 andcyclopropylmethanamine in a similar manner to compound 15-14 in Example15. ¹H NMR (400 MHz, DMSO-d6) 8.81 (s, 1H), 7.41 (brs, 1H), 7.28 (brs,1H), 6.88 (brs, 1H), 6.52 (s, 2H), 4.79 (brs, 1H), 4.53 (brs, 1H), 3.11(brs, 2H), 2.57 (s, 3H), 1.59 (brs, 3H), 1.20 (brs, 3H), 1.10 (brs, 3H),0.99-0.91 (m, 1H), 0.45 (brs, 2H), 0.22 (brs, 2H). LC-MS (M+H)⁺=460.2.RetTime in chiral-HPLC: 3.7 min, Method C

Example 43(3-((S)-1-(8-amino-1-methylimidazo[1,5-a]pyrazin-3-yl)ethyl)-5-chloro-6-fluoro-2-isopropoxyphenyl)((2S,6S)-2,6-dimethylmorpholino)methanone(Compound 43)

This compound (59 mg, 47.6%) was prepared from compound 15-13 and(2S,6S)-2,6-dimethylmorpholine in a similar manner to compound 15-14 inExample 15. ¹H NMR (400 MHz, DMSO-d6) δ 7.47 (d, J=8.8 Hz, 0.3H),7.37-7.30 (m, 1H), 7.22 (d, J=4.4 Hz, 0.7H), 7.03-6.69 (m, 3H),4.86-4.66 (m, 1H), 4.43-4.15 (m, 1H), 4.10-3.89 (m, 1H), 3.87-3.58 (m,2H), 3.40-3.33 (m, 1H), 3.09-2.94 (m, 1H), 2.92-2.72 (m, 1H), 2.60-2.51(m, 3H), 1.65 (d, J=6.9 Hz, 2H), 1.52 (d, J=6.7 Hz, 1H), 1.33-1.17 (m,4H), 1.15-1.05 (m, 4H), 0.99 (d, J=6.3 Hz, 1H), 0.90 (d, J=6.2 Hz, 1H),0.86 (d, J=5.6 Hz, 2H). LC-MS (M+H)⁺=504.2. RetTime in chiral-HPLC: 2.77min and 3.98 min, Method F.

Example 443-((S)-1-(8-amino-1-methylimidazo[1,5-a]pyrazin-3-yl)ethyl)-5-chloro-6-fluoro-2-isopropoxy-N—((R)-tetrahydro-2H-pyran-3-yl)benzamide(Compound 44)

This compound (82 mg, 68%) was prepared from compound 15-13 and(R)-tetrahydro-2H-pyran-3-amine in a similar manner to compound 15-14 inExample 15. ¹H NMR (400 MHz, DMSO-d6) δ 8.67 (d, J=7.7 Hz, 1H), 7.36 (d,J=8.6 Hz, 1H), 7.22 (d, J=5.0 Hz, 1H), 6.82 (d, J=5.0 Hz, 1H), 6.40 (s,2H), 4.76-4.71 (m, 1H), 4.48-4.37 (m, 1H), 3.85-3.77 (m, 1H), 3.76-3.70(m, 1H), 3.69-3.62 (m, 1H), 3.29-3.25 (m, 1H), 3.15-3.09 (m, 1H), 2.53(s, 3H), 1.89-1.81 (m, 1H), 1.69-1.62 (m, 1H), 1.54 (d, J=7.1 Hz, 3H),1.50-1.40 (m, 2H), 1.15 (d, J=6.1 Hz, 3H), 1.03 (d, J=6.5, 3H). LC-MS(M+H)⁺=490.1. RetTime in chiral-HPLC: 3.47 min, Method F

Example 453-((S)-1-(8-amino-1-methylimidazo[1,5-a]pyrazin-3-yl)ethyl)-5-chloro-6-fluoro-2-isopropoxy-N—((S)-tetrahydro-2H-pyran-3-yl)benzamide(Compound 45)

This compound (31 mg, 25.7%) was prepared from compound 15-13 and(S)-tetrahydro-2H-pyran-3-amine in a similar manner to compound 15-14 inExample 15. ¹H NMR (400 MHz, DMSO-d6) δ 8.71 (d, J=7.5 Hz, 1H), 7.42 (d,J=8.6 Hz, 1H), 7.30 (d, J=5.2 Hz, 1H), 6.88 (d, J=5.1 Hz, 1H), 6.73 (s,2H), 4.76-4.71 (m, 1H), 4.51-4.41 (m, 1H), 3.85-3.76 (m, 1H), 3.76-3.71(m, 1H), 3.69-3.63 (m, 1H), 3.31-3.27 (m, 1H), 3.20-3.11 (m, 1H), 2.57(s, 3H), 1.90-1.87 (m, 1H), 1.69-1.65 (m, 1H), 1.57 (d, J=7.0 Hz, 3H),1.54-1.41 (m, 2H), 1.18 (d, J=6.0 Hz, 3H), 1.06 (d, J=6.0 Hz, 3H). LC-MS(M+H)⁺=489.8. RetTime in chiral-HPLC: 9.75 min, Method D

Example 463-((S)-1-(8-amino-1-methylimidazo[1,5-a]pyrazin-3-yl)ethyl)-5-chloro-6-fluoro-N-((1S,2S)-2-hydroxycyclohexyl)-2-isopropoxybenzamide(Compound 46)

This compound (32 mg, 26%) was prepared from compound 15-13 and(1S,2S)-2-aminocyclohexan-1-ol in a similar manner to compound 15-14 inExample 15. ¹H NMR (400 MHz, DMSO-d6) δ 8.53 (d, J=7.9 Hz, 1H), 7.36 (d,J=8.5 Hz, 1H), 7.27 (d, J=5.1 Hz, 1H), 6.87 (d, J=5.1 Hz, 1H), 6.64 (s,2H), 4.81-4.74 (m, 1H), 4.69-4.58 (m, 1H), 4.48 (d, J=5.6 Hz, 1H),3.65-3.55 (m, 1H), 3.29-3.22 (m, 1H), 2.57 (s, 3H), 1.96-1.78 (m, 2H),1.65-1.59 (m, 2H), 1.56 (d, J=7.1 Hz, 3H), 1.37-1.17 (m, 4H), 1.15 (d,J=6.0 HZ, 3H), 1.02 (d, J=6.0 Hz, 3H). LC-MS (M+H)⁺=503.8. RetTime inchiral-HPLC: 3.12 min, Method F

Example 473-((S)-1-(8-amino-1-methylimidazo[1,5-a]pyrazin-3-yl)ethyl)-5-chloro-6-fluoro-N-((1S,2R)-2-hydroxycyclohexyl)-2-isopropoxybenzamide(Compound 47)

This compound (26 g, 21%) was prepared from compound 15-13 and(1R,2S)-2-aminocyclohexan-1-ol in a similar manner to compound 15-14 inExample 15. ¹H NMR (400 MHz, DMSO-d6) δ 8.36 (d, J=8.1 Hz, 1H), 7.37 (d,J===8.5 HZ, 1H), 7.31 (d, J=5.2 Hz, 1H), 6.88 (d, J=5.1 Hz, 1H), 6.79(s, 2H), 4.80-4.75 (m, 1H), 4.55-4.50 (m, 1H), 4.48 (d, J=3.6 Hz, 1H),3.90-3.82 (m, 1H), 3.80-3.75 (m, 1H), 2.57 (s, 3H), 1.72-1.63 (m, 2H),1.61-1.51 (m, 5H), 1.50-1.42 (m, 2H), 1.35-1.22 (m, 2H), 1.17 (d, J=5.9Hz, 3H), 1.04 (d, J=6.0 Hz, 3H). LC-MS (M+H)⁺=503.8. RetTime inchiral-HPLC: 6.17 min, Method D

Example 483-((S)-1-(8-amino-1-methylimidazo[1,5-a]pyrazin-3-yl)ethyl)-5-chloro-6-fluoro-N-((1R,2S)-2-hydroxycyclohexyl)-2-isopropoxybenzamide(Compound 48)

This compound (43 mg, 34.7%) was prepared from compound 15-13 and(1S,2R)-2-aminocyclohexan-1-ol in a similar manner to compound 15-14 inExample 15. ¹H NMR (400 MHz, DMSO-d6) δ 8.33 (d, J=8.1 Hz, 1H), 7.36 (d,J=8.5 Hz, 1H), 7.27 (d, J=5.2 Hz, 1H), 6.86 (d, J=5.1 Hz, 1H), 6.69 (s,2H), 4.81-4.73 (m, 1H), 4.58-4.49 (m, 1H), 4.46 (d, J=3.6 Hz, 1H),3.90-3.83 (m, 1H), 3.81-3.75 (m, 1H), 2.57 (s, 3H), 1.73-1.64 (m, 2H),1.62-1.51 (m, 5H), 1.50-1.43 (m, 2H), 1.34-1.25 (m, 2H), 1.18 (d, J=6.0Hz, 3H), 1.10 (d, J=6.0 Hz, 3H). LC-MS (M+H)⁺=503.8. Ref rime inchiral-HPLC: 6.14 min, Method D

Example 493-((S)-1-(8-amino-1-methylimidazo[1,5-a]pyrazin-3-yl)ethyl)-5-chloro-6-fluoro-N-((1R,2R)-2-hydroxycyclohexyl)-2-isopropoxybenzamide(Compound 49)

This compound (53 mg, 42.7%) was prepared from compound 15-13 and(1R,2R)-2-aminocyclohexan-1-ol in a similar manner to compound 15-14 inExample 15. ¹H NMR (400 MHz, DMSO-d6) δ 8.50 (d, J=7.9 Hz, 1H), 7.37 (d,J=8.5 HZ, 1H), 7.26 (d, J=5.1 Hz, 1H), 6.86 (d, J=5.1 Hz, 1H), 6.60 (s,2H), 4.81-4.73 (m, 1H), 4.69-4.59 (m, 1H), 4.48 (d, J=5.6 Hz, 1H),3.64-3.54 (m, 1H), 3.30-3.24 (m, 1H), 2.57 (s, 3H), 1.96-1.79 (m, 2H),1.65-1.60 (s, 2H), 1.57 (d, J=7.1 Hz, 3H), 1.33-1.17 (m, 4H), 1.16 (d,J=6.0 Hz, 3H), 1.08 (d, J=5.9 Hz, 3H). LC-MS (M+H)⁺=503.8. RetTime inchiral-HPLC: 6.63 min, Method D

Example 503-((S)-1-(8-amino-1-methylimidazo[1,5-a]pyrazin-3-yl)ethyl)-5-chloro-6-fluoro-2-isopropoxy-N-((tetrahydro-2H-pyran-3-yl)methyl)benzamide(Compound 50)

This compound (66 mg, 53%) was prepared from compound 15-13 and(tetrahydro-2H-pyran-3-yl)methanamine in a similar manner to compound15-14 in Example 15. ¹H NMR (400 MHz, DMSO-d6) δ 8.66 (t, J=5.8 Hz, 1H),7.39 (d, J=8.6 Hz, 1H), 7.28 (d, J=5.2 Hz, 1H), 6.83 (d, J=5.1 Hz, 1H),6.73 (s, 2H), 4.78-4.70 (m, 1H), 4.45-4.35 (m, 1H), 3.76-3.70 (m, 1H),3.69-3.63 (m, 1H), 3.26-3.22 (m, 1H), 3.09-3.02 (m, 3H), 2.53 (s, 3H),1.78-1.65 (m, 2H), 1.54 (d, J=7.1 Hz), 1.51-1.48 (m, 1H), 1.45-1.33 (m,1H), 1.22-1.17 (m, 1H), 1.14 (d, J=6.1 HZ, 3H), 1.04 (d, J=6.0 Hz, 3H).LC-MS (M+H)⁺+504.2. RetTime in chiral-HPLC: 3.31 min, Method F

Example 51(S)-3-(1-(8-amino-1-methylimidazo[1,5-a]pyrazin-3-yl)ethyl)-5-chloro-6-fluoro-2-isopropoxy-N-((tetrahydro-2H-pyran-4-yl)methyl)benzamide(Compound 51)

This compound (61 mg, 49%) was prepared from compound 15-13 and(tetrahydro-2H-pyran-4-yl)methanamine in a similar manner to compound15-14 in Example 15. ¹H NMR (400 MHz, DMSO-d6) δ 8.69 (t, J=5.7 Hz, 1H),7.40 (d, J=8.6 Hz, 1H), 7.29 (d, J=5.2 Hz, 1H), 6.84 (d, J=5.2 Hz, 1H),6.79 (s, 2H), 4.80-4.71 (m, 1H), 4.47-4.36 (m, 1H), 3.84-3.78 (m, 2H),3.24-3.17 (m, 2H), 3.08 (t, J=6.3 Hz, 2H), 2.54 (s, 3H), 1.74-1.64 (m,1H), 1.59-1.50 (m, 5H), 1.21-1.11 (m, 5H), 1.04 (d, J=6.1 Hz, 3H). LC-MS(M H)⁺=504.2. RetTime in chiral-HPLC: 4.68 min, Method L.

Example 52(3-((S)-1-(8-amino-1-methylimidazo[1,5-a]pyrazin-3-yl)ethyl)-5-chloro-6-fluoro-2-isopropoxyphenyl)(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)methanone(Compound 52)

This compound (32 mg, 26%) was prepared from compound 15-13 and8-oxa-3-azabicyclo[3.2.1]octane in a similar manner to compound 15-14 inExample 15. ¹H NMR (400 MHz, DMSO-d6) δ 7.50-7.33 (m, 1H), 7.31-7.11 (m,1H), 6.91-6.81 (m, 0.6H), 6.80-6.70 (m, 0.4H), 6.55-6.31 (m, 2H),4.85-4.66 (m, 1H), 4.64-4.51 (m, 0.4H), 4.42 (brs, 1H), 4.33-3.99 (m,2.6H), 3.29-3.23 (m, 1H), 3.16-3.03 (m, 1H), 3.03-2.78 (m, 2H), 2.57 (s,3H), 1.87 (brs, 2H), 1.77-1.63 (m, 3H), 1.58-1.49 (m, 1H), 1.37-1.10 (m,6H), 0.96-0.77 (m, 1H). LC-MS (M+H)⁺=501.8. RetTime in chiral-HPLC: 5.17min, Method B.

Example 533-((S)-1-(8-amino-1-methylimidazo[1,5-a]pyrazin-3-yl)ethyl)-5-chloro-6-fluoro-N-((1R,3R)-3-hydroxycyclopentyl)-2-isopropoxybenzamide(Compound 53)

This compound (45 mg, 37.5%) was prepared from compound 15-13 and(1R,3R)-3-aminocyclopentan-1-ol in a similar manner to compound 15-14 inExample 15. ¹H NMR (400 MHz, DMSO-d6) δ 8.67 (d, J=7.5 Hz, 1H), 7.45 (d,J=8.6 Hz, 1H), 7.40 (d, J=5.4 Hz, 1H), 7.38-7.25 (m, 2H), 6.92 (d, J=5.3Hz, 1H), 4.84-4.76 (m, 1H), 4.54 (d, J=3.6 Hz, 1H), 4.50-4.41 (m, 1H),4.39-4.30 (m, 1H), 4.19-4.13 (m, 1H), 2.58 (s, 3H), 2.07-1.97 (m, 1H),1.84 (d, J=3.9 Hz, 2H), 1.61-1.54 (m, 4H), 1.50-1.35 (m, 2H), 1.17 (d,J=6.1 Hz, 3H), 1.05 (d, J=6.1 Hz, 3H). LC-MS (M+H)⁺=489.8. RetTime inchiral-HPLC: 3.45 min, Method B

Example 54(S)-3-(1-(8-amino-1-methylimidazo[1,5-a]pyrazin-3-yl)ethyl)-5-chloro-N-(1-((dimethylamino)methyl)cyclopropyl)-6-fluoro-2-isopropoxybenzamide(Compound 54)

This compound (33 mg, 26.6%) was prepared from compound 15-13 and1-((dimethylamino)methyl)cyclopropan-1-amine in a similar manner tocompound 15-14 in Example 15. ¹H NMR (400 MHz, DMSO-d6) δ 9.21 (s, 1H),7.52 (d, J=8.6 Hz, 1H), 7.38 (d, J=5.2 Hz, 1H), 7.03 (s, 2H), 6.91 (d,J=5.2 Hz, 1H), 4.83-4.74 (m, 1H), 4.38-4.24 (s, 1H), 3.30-3.17 (m, 2H),2.77 (s, 6H), 2.57 (s, 3H), 1.58 (d, J=7.0 Hz, 3H), 1.20-1.11 (m, 5H),1.05 (d, J=6.0 Hz, 3H), 0.93-0.78 (m, 2H). LC-MS (M+H)⁺=502.8. RetTimein chiral-HPLC: 3.57 min, Method A

Example 55(S)-3-(1-(8-amino-1-methylimidazo[1,5-a]pyrazin-3-yl)ethyl)-5-chloro-6-fluoro-N-((3-hydroxyoxetan-3-yl)methyl)-2-isopropoxybenzamide(Compound 55)

This compound (51 mg, 42%) was prepared from compound 15-13 and3-(aminomethyl)oxetan-3-ol in a similar manner to compound 15-14 inExample 15. ¹H NMR (400 MHz, DMSO-d6) δ 8.87 (t, J=5.7 Hz, 1H), 7.41 (d,J=8.5 Hz, 1H), 7.30 (d, J=5.2 Hz, 1H), 6.88 (d, J=5.1 Hz, 1H), 6.80 (s,2H), 5.87 (s, 1H), 4.83-4.73 (m, 1H), 4.54-4.74 (m, 1H), 4.47-4.42 (m,2H), 4.41-4.36 (m, 2H), 3.64-3.48 (m, 2H), 2.58 (s, 3H), 1.58 (d, J=7.0HZ, 3H), 1.18 (d, J=6.0 Hz, 3H), 1.08 (d, J=6.0 Hz, 3H). LC-MS(M+H)⁺=491.8. RetTime in chiral-HPLC: 5.8 min, Method B.

Example 56(S)-3-(1-(8-amino-1-methylimidazo[1,5-a]pyrazin-3-yl)ethyl)-5-chloro-N-(1-((4-(cyclopropylmethyl)piperazin-1-yl)methyl)cyclopropyl)-6-fluoro-2-isopropoxybenzamide(Compound 56)

This compound (55 mg, 37.4%) was prepared from compound 15-13 and1-((4-(cyclopropylmethyl)piperazin-1-yl)methyl)cyclopropan-1-amine in asimilar manner to compound 15-14 in Example 15. ¹H NMR (400 MHz,DMSO-d6) δ 8.83 (s, 1H), 7.34 (d, J=8.5 Hz, 1H), 7.24 (d, J=5.0 Hz, 1H),6.85 (d, J=5.0 Hz, 1H), 6.43 (s, 2H), 4.81-4.72 (m, 1H), 4.71-4.61 (m,1H), 3.33-3.24 (m, 2H), 2.56 (s, 3H), 2.47-2.23 (m, 7H), 2.13 (d, J=6.4HZ, 2H), 1.56 (d, J=7.0 Hz, 3H), 1.18 (d, J=5.9 Hz, 3H), 1.07 (d, J=5.9Hz, 3H), 0.82-0.74 (m, 1H), 0.73-0.69 (m, 2H), 0.68-0.60 (m, 2H),0.47-0.37 (m, 2H), 0.08-0.01 (m, 2H). LC-MS (M+H)⁺=597.8. RetTime inchiral-HPLC: 2.6 min, Method B.

Example 573-((S)-1-(8-amino-1-methylimidazo[1,5-a]pyrazin-3-yl)ethyl)-5-chloro-6-fluoro-N—((S)-2-hydroxypropyl)-2-isopropoxybenzamide(Compound 57)

This compound (19 mg, 16.7%) was prepared from compound 15-13 and(S)-1-aminopropan-2-ol in a similar manner to compound 15-14 in Example15. ¹H NMR (400 MHz, DMSO-d6) δ 8.67 (t, J=5.6 Hz, 1H), 7.41 (d, J=8.5Hz, 1H), 7.32 (d, J=5.0 HZ, 1H), 7.00-6.70 (m, 3H), 4.88-4.74 (m, 1H),4.70 (d, J=4.6 Hz, 1H), 4.54-4.42 (m, 1H), 3.78-3.66 (m, 1H), 3.24-3.16(m, 1H), 3.15-3.07 (m, 1H), 2.58 (s, 3H), 1.58 (d, J=7.0 Hz, 3H), 1.18(d, J=6.0 Hz, 3H), 1.07 (t, J=5.6 Hz, 6H). LC-MS (M+H)⁺=463.8. RetTimein chiral-HPLC: 3.02 min, Method B.

Example 583-((S)-1-(8-amino-1-methylimidazo[1,5-a]pyrazin-3-yl)ethyl)-5-chloro-6-fluoro-N-((1R,2R)-2-hydroxycyclopentyl)-2-isopropoxybenzamide(Compound 58)

This compound (81 mg, 67%) was prepared from compound 15-13 and(1R,2R)-2-aminocyclopentan-1-ol in a similar manner to compound 15-14 inExample 15. ¹H NMR (400 MHz, DMSO-d6) δ 8.57 (d, J=7.2 Hz, 1H), 7.39 (d,J=8.6 Hz, 1H), 7.28 (d, J=5.2 Hz, 1H), 6.85 (d, J=5.1 Hz, 1H), 6.69 (s,2H), 4.81-4.71 (m, 2H), 4.53-4.43 (m, 1H), 3.98-3.85 (m, 2H), 2.55 (s,3H), 2.01-1.91 (m, 1H), 1.80-1.70 (m, 1H), 1.68-1.59 (m, 2H), 1.55 (d,J=7.1 Hz, 3H), 1.48-1.33 (m, 2H), 1.16 (d, J=6.1 Hz, 3H), 1.04 (d, J=6.0Hz, 3H). LC-MS (M+H)⁺=489.8. RetTime in chiral-HPLC: 2.99 min, Method B.

Example 593-((S)-1-(8-amino-1-methylimidazo[1,5-a]pyrazin-3-yl)ethyl)-5-chloro-6-fluoro-2-isopropoxy-N—((S)-1-(2-(trifluoromethyl)pyridin-4-yl)ethyl)benzamide(Compound 59A) and3-((S)-1-(8-amino-1-methylimidazo[1,5-a]pyrazin-3-yl)ethyl)-5-chloro-6-fluoro-2-isopropoxy-N—((R)-1-(2-(trifluoromethyl)pyridin-4-yl)ethyl)benzamide(Compound 59B)

These compounds were prepared from compound 15-13 and1-(2-(trifluoromethyl)pyridin-4-yl)ethan-1-amine in a similar manner tocompound 15-14 in Example 15, The isomers were obtained by chiralseparation.

Compound 59A: 136 mg, 31.9%. ¹H NMR (400 MHz, DMSO-d6) δ 9.42 (d, J=7.6Hz, 1H), 8.77 (d, J=5.0 Hz, 1H), 7.89 (s, 1H), 7.71 (d, J=4.9 Hz, 1H),7.49 (d, J=8.7 Hz, 1H), 7.29 (d, J=5.1 Hz, 1H), 6.86 (d, J=5.0 Hz, 1H),6.46 (s, 2H), 5.26-5.16 (m, 1H), 4.81-4.73 (m, 1H), 4.27-4.16 (m, 1H),2.56 (s, 3H), 1.57 (d, J=7.1 Hz, 3H), 1.43 (d, J=7.1 Hz, 3H), 1.07 (d,J=6.1 Hz, 3H), 0.93 (d, J=6.1 Hz, 3H). LC-MS (M+H)⁺=578.7. RetTime inchiral-HPLC: 3.68 min, Method. C.

Compound 59B: 103 mg, 24%, ¹H NMR (400 MHz, DMSO-d6) δ 9.42 (d, J=7.5Hz, 1H), 8.77 (d, J=4.6 Hz, 1H), 7.89 (s, 1H), 7.72 (d, J=4.1 Hz, 1H),7.46 (d, J=8.5 Hz, 1H), 7.28 (d, J=4.7 Hz, 1H), 6.85 (d, J=4.7 Hz, 1H),6.47 (s, 2H), 5.29-5.17 (m, 1H), 4.82-4.69 (m, 1H), 4.32-4.18 (m, 1H),2.56 (s, 3H), 1.59 (d, J=6.8 Hz, 3H), 1.43 (d, J=6.8 Hz, 3H), 1.06 (d,J=5.7 Hz, 3H), 0.89 (d, J=5.7 Hz, 3H). LC-MS (M+H)⁺=578.7. RetTime inchiral-HPLC: 4.18 min., Method C.

Column CHIRALPAK ID Column size 2 cm × 25 cm, 5 um Injection 0.3 mlMobile phase Hex(10 mM NH₃—MeOH):EtOH = 80:20 Flow rate 20 mL/min Wavelength UV 220 nm Temperature 25° C. Sample solution 58 mg/mL in EtOH:DCM= 3:1 Prep-HPLC equipment Prep-HPLC-Gilson

Example 603-((S)-1-(8-amino-1-methylimidazo[1,5-a]pyrazin-3-yl)ethyl)-5-chloro-6-fluoro-N-((trans)-4-hydroxycyclohexyl)-2-isopropoxybenzamide(Compound 60)

This compound (50 mg, 39%) was prepared from compound 15-13 andtrans-4-aminocyclohexan-1-ol in a similar manner to compound 15-14 inExample 15. ¹H NMR (400 MHz, DMSO-d6) δ 8.57 (d, J=7.8 Hz, 1H), 7.38 (d,J=8.6 Hz, 1H), 7.25 (d, J=5.1 Hz, 1H), 6.85 (d, J=5.0 Hz, 1H), 6.42(brs, 2H), 4.76 (q, J=7.2 Hz, 1H), 4.55 (d, J=4.3 Hz, 1H), 4.51-4.43 (m,1H), 3.65 (brs, 1H), 3.34 (brs, 1H), 2.56 (s, 3H), 1.87-1.76 (m, 4H),1.56 (d, J=7.1 Hz, 3H), 1.28-1.20 (m, 4H), 1.17 (d, J=6.0 Hz, 3H), 1.06(d, J=6.0 Hz, 3H). LC-MS (M+H)⁺=504.2. RetTime in chiral-HPLC: 4.372min, Method C.

Example 613-((S)-1-(8-amino-1-methylimidazo[1,5-a]pyrazin-3-yl)ethyl)-5-chloro-6-fluoro-N-((trans)-3-hydroxycyclobutyl)-2-isopropoxybenzamide(Compound 61)

This compound (80 mg, 75%) was prepared from compound 15-13 andtrans-3-aminocyclobutan-1-ol in a similar manner to compound 15-14 inExample 15. ¹H NMR (400 MHz, DMSO-d6) δ 8.96 (brs, 1H), 7.45 (d, J=8.7Hz, 1H), 7.32 (brs, 1H), 6.89 (brs, 1H), 6.72 (brs, 2H), 5.09 (brs, 1H),4.79 (brs, 1H), 4.44 (brs, 1H), 4.28 (brs, 2H), 2.58 (s, 3H), 2.16 (brs,4H), 1.58 (brs, 3H), 1.19 (brs, 3H), 1.07 (brs, 3H). LC-MS (M+H)⁺=476.2.RetTime in chiral-HPLC: 2.669 min, Method K.

Example 623-((S)-1-(8-amino-1-methylimidazo[1,5-a]pyrazin-3-yl)ethyl)-5-chloro-6-fluoro-N-((cis)-4-hydroxycyclohexyl)-2-isopropoxybenzamide(Compound 62)

This compound (70 mg, 55%) was prepared from compound 15-13 andcis-4-aminocyclohexan-1-ol in a similar manner to compound 15-14 inExample 15. ¹H NMR (400 MHz, DMSO-d6) δ 8.61 (brs, 1H), 7.35 (d, J=8.4Hz, 1H), 7.25 (brs, 1H), 6.85 (brs, 1H), 6.50 (brs, 2H), 4.76 (brs, 1H),4.48 (brs, 1H), 4.38 (brs, 1H), 3.75 (brs, 1H), 3.66 (brs, 1H), 2.55(brs, 3H), 1.69-1.41 (m, 8H), 1.17 (brs, 3H), 1.05 (brs, 3H). LC-MS(M+H)⁺=504.2. RetTime in chiral-HPLC: 2.045 min, Method L.

Example 633-((S)-1-(8-amino-1-methylimidazo[1,5-a]pyrazin-3-yl)ethyl)-5-chloro-6-fluoro-N-((cis)-3-hydroxycyclobutyl)-2-isopropoxybenzamide(Compound 63)

This compound (70 mg, 59%) was prepared from compound 15-13 andcis-3-aminocyclobutan-1-ol in a similar manner to compound 15-14 inExample 15. ¹H NMR (400 MHz, DMSO-d6) δ 8.89 (brs, 1H), 7.44 (d, J=8.3Hz, 1H), 7.32 (brs, 1H), 6.89 (brs, 1H), 6.81 (brs, 2H), 5.13 (brs, 1H),4.79 (brs, 1H), 4.42 (brs, 1H), 3.82 (brs, 2H), 2.59-2.51 (m, 5H), 1.77(brs, 2H), 1.58 (brs, 3H), 1.19 (brs, 3H), 1.07 (brs, 3H). LC-MS(M+H)⁺=476.2. HPLC: 214 nm, 98%; 254 nm, 98%. RetTime in chiral-HPLC:3.358 min. RetTime in chiral-HPLC: 3.36 min, Method F.

Example 64(S)-(3-(1-(8-amino-1-methylimidazo[1,5-a]pyrazin-3-yl)ethyl)-5-chloro-6-fluoro-2-isopropoxyphenyl)(2-oxa-7-azaspiro[3,5]nonan-7-yl)methanone(Compound 64)

This compound (70 mg, 54%) was prepared from compound 15-13 and2-oxa-7-azaspiro[3.5]nonane oxalate in a similar manner to compound15-14 in Example 15. ¹H NMR (400 MHz, DMSO-d6) δ 7.41 (d, J=6.5 Hz,0.3H), 7.31 (d, J=6.5 Hz, 0.7H), 7.25 (brs, 0.3H), 7.16 (brs, 0.7H),6.85 (brs, 1H), 6.56 (brs, 2H), 4.74 (brs, 1H), 4.43-4.17 (m, 4.7H),3.76 (brs, 0.6H), 3.57 (brs, 0.6H), 3.34 (brs, 0.8H), 3.14 (brs, 0.8H),2.95 (brs, 1.5H), 2.59-2.53 (m, 3H), 1.87 (brs, 1H), 1.82-1.60 (m, 5H),1.57-1.52 (brs, 1H), 1.20 (brs, 4H), 1.13 (brs, 1H), 0.95 (brs, 1H).LC-MS (M+H)⁺=516.2. RetTime in chiral-HPLC: 6.206 min, Method F

Example 65(3-((S)-1-(8-amino-1-methylimidazo[1,5-a]pyrazin-3-yl)ethyl)-5-chloro-6-fluoro-2-isopropoxyphenyl)((S)-3-methoxypiperidin-1-yl)methanone(Compound 65)

This compound (70 mg, 55%) was prepared from compound 15-13 and(S)-3-methoxypiperidine in a similar manner to compound 15-14 in Example15. ¹H NMR (400 MHz, DMSO-d6) δ 7.51-7.22 (m, 2H), 7.00 (brs, 2H),6.92-6.79 (m, 1H), 4.87-4.72 (m, 1H), 4.57-4.46 (m, 0.3H), 4.46-4.34 (m,0.6H), 4.30-4.21 (m, 0.2H), 4.14 (d, J=13.2 Hz, 0.3H), 4.06-3.94 (m,0.5H), 3.60 (brs, 0.3H), 3.52-3.40 (m, 0.7H), 3.31 (s, 1.5H), 3.27 (s,1H), 3.24-3.10 (m, 1H), 3.08-2.88 (m, 2.5H), 2.58 (brs, 3H), 2.02-1.78(m, 1H), 1.77-1.60 (m, 3H), 1.60-1.52 (m, 1.5H), 1.51-1.29 (m, 1.5H),1.29-1.12 (m, 4.8H), 0.97 (d, J=5.9 Hz, 0.8H), 0.88 (d, J=5.8 Hz, 0.4H).LC-MS (M+H)⁺=516.2. RetTime in chiral-HPLC: 6.817 min, Method G.

Example 66(S)-3-(1-(8-amino-1-methylimidazo[1,5-a]pyrazin-3-yl)ethyl)-5-chloro-6-fluoro-N-((1-hydroxycyclopropyl)methyl)-2-isopropoxybenzamide(Compound 66)

This compound (50 mg, 42%) was prepared from compound 15-13 and1-(aminomethyl)cyclopropan-1-ol in a similar manner to compound 15-14 inExample 15. ¹H NMR (400 MHz, DMSO-d6) δ 8.74 (t, J=5.7 Hz, 1H), 7.42 (d,J=8.5 Hz, 1H), 7.35 (d, J=5.3 Hz, 1H), 7.08 (brs, 2H), 6.89 (d, J=5.2Hz, 1H), 5.28 (s, 1H), 4.80 (q, J=7.0 Hz, 1H), 4.60-4.51 (m, 1H), 3.39(d, J=5.9 Hz, 2H), 2.58 (s, 3H), 1.58 (d, J=7.0 Hz, 3H), 1.18 (d, J=6.0Hz, 3H), 1.08 (d, J=6.0 Hz, 3H), 0.54 (brs, 4H). LC-MS (M+H)⁺=476.1.RetTime in chiral-HPLC: 3.187 min, Method F.

Example 67(3-((S)-1-(8-amino-1-methylimidazo[1,5-a]pyrazin-3-yl)ethyl)-5-chloro-6-fluoro-2-isopropoxyphenyl)((2R,6S)-2,6-dimethylmorpholino)methanone(Compound 67)

This compound (40 mg, 31%) was prepared from compound 15-13 and(2R,6S)-2,6-dimethylmorpholine in a similar manner to compound 15-14 inExample 15. ¹H NMR (400 DMSO-d6) δ 7.51-7.41 (m, 0.6H), 7.36-7.28 (m,0.6H), 7.26 (d, J=5.2 Hz, 0.4H), 7.22 (d, J=5.1 Hz, 0.4H), 6.87 (d,J=5.1 Hz, 0.3H); 6.84-6.80 (m, 0.7H), 6.64 (brs, 2H), 4.82-4.72 (m, 1H),4.53-4.33 (m, 1.5H), 4.32-4.22 (m, 0.4H), 4.15-4.07 (m, 0.2H), 3.52(brs, 1.9H), 3.02 (d, J=12.0 Hz, 0.5H), 2.90-2.72 (m, 1H), 2.70-2.6.4(m, 0.5H), 2.60-2.56 (m, 3H), 2.49-2.43 (m, 1H), 1.68 (t, J=6.9 Hz,2.2H), 1.59-1.54 (m, 0.8H), 1.29 (d, J=6.0 Hz, 1H), 1.27-1.21 (m, 4H),1.18-1.12 (m, 3H), 1.08-1.00 (m, 1H), 0.97-0.85 (m, 3H). LC-MS(M+H)⁺=503.8. RetTime in chiral-HPLC: 2.602 min, Method F.

Example 68(S)-(3-(1-(8-amino-1-methylimidazo[1,5-a]pyrazin-3-yl)ethyl-5-chloro-6-fluoro-2-isopropoxyphenyl)(6-oxa-2-azaspiro[3.4]octan-2-yl)methanone(Compound 68)

This compound (40 mg, 31%) was prepared from compound 15-13 and6-oxa-2-azaspiro[3.4]octane oxalate in a similar manner to compound15-14 in Example 15. ¹H NMR (400 MHz, DMSO-d6) δ 7.41 (d, J=8.4 Hz, 1H),7.30-7.26 (m, 1H), 6.83 (brs, 1H), 6.69 (brs, 2H), 4.82-4.74 (m, 1H),4.35 (brs, 1H), 4.04 (brs, 2H), 3.87-3.61 (m, 6H), 2.57 (s, 3H),2.22-2.00 (m, 2H), 1.65 (brs, 3H), 1.23 (d, J=10.2 Hz, 6H). LC-MS(M+H)⁺=501.8. RetTime in chiral-HPLC: 11.092 min, Method A.

Example 69(3-((S)-1-(8-amino-1-methylimidazo[1,5-a]pyrazin-3-yl)ethyl)-5-chloro-6-fluoro-2-isopropoxyphenyl)((R)-3-methoxypiperidin-1-yl)methanone(Compound 69)

This compound (70 mg, 55%) was prepared from compound 15-13 and(R)-3-methoxypiperidine in a similar manner to compound 15-14 in Example15. ¹H NMR (400 MHz, DMSO-d6) δ 7.48-7.27 (m, 2H), 7.07 (brs, 2H),6.92-6.80 (m, 1H), 4.86-4.72 (m, 1H), 4.58-4.48 (m, 0.5H), 4.45-4.30 (m,0.5H), 4.30-4.12 (m, 0.5H), 3.82-3.37 (m, 2H), 3.29 (brs, 2H), 3.23-3.10(m, 1.5H), 3.10-2.88 (m, 1.5H), 2.83 (brs, 0.5H), 2.60-2.56 (m, 3H),1.89 (brs, 1H), 1.79-1.62 (m, 4H), 1.63-1.53 (m, 1H), 1.32-1.14 (m, 6H),1.06-1.02 (m, 0.4H), 0.99-0.92 (m, 0.6H). LC-MS (M+H)⁺=501.8, RetTime inchiral-HPLC: 5.630 min, Method A.

Example 70(3-((S)-1-(8-amino-1-methylimidazo[1,5-a]pyrazin-3-yl)ethyl)-5-chloro-6-fluoro-2-isopropoxyphenyl)((S)-3-methoxypyrrolidin-1-yl)methanone(Compound 70)

This compound (70 mg, 57%) was prepared from compound 15-13 and(S)-3-methoxypyrrolidine in a similar manner to compound 15-14 inExample 15. ¹H NMR (400 MHz, DMSO-d6) δ 7.50-7.24 (m, 2H), 7.19-6.74 (m,3H), 4.85-4.75 (m, 1H), 4.47-4.33 (m, 0.6H), 4.33-4.20 (m, 0.4H),4.09-3.92 (m, 0.6H), 3.88 (brs, 0.4H), 3.68-3.37 (m, 2H), 3.27-2.91 (m,5H), 2.65-2.54 (m, 3H), 1.97 (brs, 2H), 1.65 (brs, 2H), 1.54 (brs, 1H),1.26-1.14 (m, 5H), 0.94-0.84 (m, 1H). LC-MS (M+H)⁺=501.8. RetTime inchiral-HPLC: 3.679 min, Method F.

Example 713-((S)-1-(8-amino-1-methylimidazo[1,5-a]pyrazin-3-yl)ethyl)-5-chloro-6-fluoro-N-((1S,3S)-3-hydroxycyclopentyl)-2-isopropoxybenzamide(Compound 71)

This compound (49 mg, 40%) was prepared from compound 15-13 and(1S,3S)-3-aminocyclopentan-1-ol in a similar manner to compound 15-14 inExample 15. ¹H NMR (400 MHz, DMSO-d6) δ 8.67 (d, J=7.6 Hz, 1H), 7.45 (d,J=8.6 Hz, 1H), 7.41-7.24 (m, 3H), 6.92 (d, J=5.3 Hz, 1H), 4.81 (q, J=7.0Hz, 1H), 4.57-4.51 (m, 1H), 4.50-4.40 (m, 1H), 4.40-4.30 (m, 1H), 4.17(brs, 1H), 2.58 (s, 3H), 2.09-1.97 (m, 1H), 1.91-1.78 (m, 2H), 1.63-1.54(m, 4H), 1.50-1.34 (m, 2H), 1.18 (d, J=6.0 Hz, 3H), 1.06 (d, J=6.0 Hz,3H). LC-MS (M+H)⁺=489.8. RetTime in chiral-HPLC: 6.423 min, Method A.

Example 723-((S)-1-(8-amino-1-methylimidazo[1,5-a]pyrazin-3-yl)ethyl)-5-chloro-6-fluoro-N-((2R,3R)-3-hydroxybutan-2-yl)-2-isopropoxybenzamide(Compound 72)

This compound (80 mg, 66%) was prepared from compound 15-13 and(2R,3R)-3-aminobutan-2-ol in a similar manner to compound 15-14 inExample 15. ¹H NMR (400 MHz, DMSO-d6) δ 8.42 (d, J=8.2 Hz, 1H), 7.40 (d,8.6 Hz, 1H), 7.31 (d, J=5.1 Hz, 1H), 6.88 (d, J=5.1 Hz, 1H), 6.79 (brs,2H), 4.79 (q, J=6.7 Hz, 1H), 4.61 (d, J=5.0 Hz, 1H), 4.56-4.46 (m, 1H),3.97-3.88 (m, 1H), 3.73-3.64 (m, 1H), 2.57 (s, 3H), 1.57 (d, J=7.1 Hz,3H), 1.17 (d, J=6.0 Hz, 3H), 1.08-1.03 (m, 6H), 1.02 (d, J=6.3 Hz, 3H).LC-MS (M+H)⁺=477.8. RetTime in chiral-HPLC: 3.655 min, Method C.

Example 73(S)-3-(1-(8-amino-1-methylimidazo[1,5-a]pyrazin-3-yl)ethyl)-5-chloro-6-fluoro-2-isopropoxy-N-(2-(4-methylpiperazin-1-yl)ethyl)benzamide(Compound 73)

This compound (93 mg, 72.1%) was prepared from compound 15-13 and2-(4-methylpiperazin-1-yl)ethan-1-amine in a similar manner to compound15-14 in Example 15. 1H NMR (400 MHz, DMSO-d6) δ 8.64-8.61 (t, 1H),7.39-7.37 (d, J=8.8 Hz, 1H), 7.25-7.24 (d, J=5.2 Hz, 1H), 6.86-6.85 (d,J=4.8 Hz, 1H), 6.43 (brs, 2H), 4.80-4.74 (m, 1H), 4.52-4.46 (m, 1H),3.41-3.28 (m, 4H), 2.56 (s, 3H), 2.43-2.18 (m, 8H), 2.14 (s, 3H),1.59-1.57 (d, J=6.8 Hz, 3H), 1.19-1.18 (d, J=5.6 Hz, 3H), 1.10-1.08 (d,J=5.6 Hz, 3H). LC-MS (M+H)⁺=532.1. HPLC: 214 nm, 96.79%; 254 nm, 100%.RetTime in chiral-HPLC: 3.67 min, Method B.

The following compounds were prepared in a similar manner:

Biological AssaysI. PI3Kδ Assay

Compounds disclosed herein were tested for inhibition of PI3Kδ kinaseactivity using commercial ADP-Glo™ Kinase Assay (Promega Corporation)and following the manufacture's instruction. Briefly, recombinant PI3K(p110δ/p85α) enzyme, lipid kinase substrate and a serial dilution ofcompounds disclosed herein were incubated for 0.5 hr at roomtemperature. ATP was added to initiate the kinase reaction, Afterincubation for 1 hr at room temperature, ADP-Glo™ reagent was added toterminate the kinase reaction and deplete the remaining ATP. Afterincubation for 1 hr at room temperature, kinase detection reagent wasadded to simultaneously convert ADP to ATP and allow the newlysynthesized ATP to be measured using a luciferase/luciferin reaction.After incubation for 0.5 hr at room temperature, the luminescencegenerated was measured on a PHERAstar FS plate reader (BMG LABTECH). Theresidual enzyme activity in presence of increasing concentrations ofcompounds was calculated based on the luminescence. The IC₅₀ for eachcompound was derived from fitting the data to the four-parameterlogistic equation by Graphpad Prism software. IC₅₀ of examples ispresented in Table 1 as determined by the PI3K delta assay.

II. PI3Kα, β and γ Assays

Compounds disclosed herein were tested for inhibition of recombinantPI3K (p110α/p85α), PI3K (p110β/p85α) and PI3K (p110γ) using the samemethod as PI3K(p110δ/p85α) except that incubation of 2 hrs was appliedto PI3K (p110β/p85α) kinase reaction. Selectivity of examples ispresented in Table 1 as determined by PI3K alpha, beta and gamma assays.

TABLE 1 Enzyme Activity IC₅₀ or max inhibition (%) at 0.5 μM for thecompounds disclosed herein Enzyme activity IC₅₀ (nM) or max inhibition(%) at 0.5 μM Compound PI3Kα PI3Kβ PL3Kβ PI3Kγ  1 >50000 >50000 9.7 9800 2 >50000 >50000 14 5500  3 49000 34000 6.3 19000  4 25000 24000 1.93100   4A 13000 11000 1.0 2000   4B — — >1000 —  5 56000 16000 3.3 10000  5A 21000 20000 1.5 6300   5B — — 93 —  6 >50000 >50000 2.9 17000 7 >50000 >50000 6.0 17000  8 49000 16000 2.3 6800  9 43000 18000 2.99200 10 34000 22000 3.0 9000 11 31000 6200 2.0 7300 12 >50000 >50000 3.714000  13A 20000 >50000 3.0 9300  13B — — >1000 —  14A 18000 13000 1.47900  14B — — 320 — 15 36000 >50000 1.8 6700 16 20000 17000 4.0 11000 1777000 72000 3.8 14000 18 19000 12000 2.4 6500 19 33000 60000 2.0 1000020 — — 2.1 — 21 33000 28000 1.4 3900 22 — — 3.7 — 23 — — 9.9 — 24 3600016000 1.6 5800 25 24000 8700 1.9 6000 26 24000 17000 0.86 6500 27 320003000 0.93 3900 28 24000 6800 1.2 4800 29 11000 9900 1.1 2100 30 1700014000 0.97 7700 31 25000 16000 3.1 6200 32 — — 3.2 — 33 9300 13000 1.32200 34 36000 11000 1.4 3200 35 46000 19000 1.3 6000 36 9500 13000 2.0460 37 11000 11000 0.56 2500 38 6100 25000 1.4 3200 39 10000 2300 0.9028000 40 — — 6.5 — 41 20000 4900 0.99 5500 42 36000 21000 1.2 4800 4321000 >50000 2.2 3400 44 20000 30000 0.74 5000 45 16000 32000 1.1 280046 9700 39000 0.94 2100 47 27000 26000 2.5 5800 48 — — 9.1 — 49 — — 3.9— 50 15000 20000 1.2 6100 51 27000 6400 0.97 4500 52 10000 40000 1.42500 53 14000 11000 0.68 2400 54 — — 11 — 55 13000 11000 1.8 2200 5628000 44000 1.9 4500 57 18000 12000 1.1 4900 58 14000 16000 2.2 2800 59A 8300 14000 2.1 1200  59B 14000 26000 1.5 2800 60 11000 35000 0.956300 61 21000 12000 1.4 4500 62 17000 29000 1.4 9000 63 38000 7400 1.14200 64 >50000 >50000 1.6 14000 65 50000 >50000 2.9 6900 66 14000 120002.2 3400 67 — — 8.0 — 68 40000 23000 1.7 4600 69 >50000 >50000 2.0 520070 41000 >50000 1.9 6700 71 14000 13000 1.4 3400 72 — — 6.8 — 73 1400014000 2.8 9500

The following assays were also used to determine the pharmacokinetic(PK) data and the blood-brain barrier (BBB) data of some exemplifiedcompounds disclosed herein.

III. Pharmacokinetic properties of compounds in Sprague-Dawley ratsafter intravenous (IV) and oral administrations (PO)

Dose Formulation Preparation

The injection dosing solution was prepared as follows: 1.0 mg of a testcompound was weighed and dissolved in 0.32 mL of dimethyl acetamide(DMA). The solution was then further diluted by 0.36 mL of ethanol and0.32 mL of propylene glycol. The final concentration of the testcompound was 1.0 mg·mL⁻¹.

The oral dosing solution was prepared as follows: 5.0 mg of a testcompound was weighed and dispersed in 10 mL of 0.5% methyl cellulose(MC). The final concentration of the test compound is 1 mg·mL⁻¹.

Animals

Male Sprague-Dawley rats (also summarized in Table 2) were housed insolid bottom polypropylene cages with sterilized bedding and receivesterilized diet and sterilized water. The room was controlled andmonitored for humidity (targeted mean range 40% to 70%) and temperature(targeted mean range 18° C. to 26° C.) with 10 to 20 air changes/hour.The light cycle was maintained at 12-h light and 12-h dark. Only animalsthat appeared to be healthy were selected for this study based onoverall health, body weight, or other relevant information. The animalswere treated in accordance with a certain treatment schedule assummarized in Table 3.

TABLE 2 Animal Information Genus Gender Species Source Age Weight (g)Reserved Selected Rat Male Sprague Dawley (SD) Vital River 8 weeks220-250 7 6

TABLE 3 Animal Treatment Schedule Dose Level Conc. Dosing Fasted/Sampling Groups Quantity (mg · kg⁻¹) (mg · mL⁻¹) Vehicle Route RegimenFed Time 1-3 3 1.0 1.0 32% DMA, 36% Tail Single Fasted Pre-dose, 5,ethanol, 32% Vein IV 15, 30 min, propylene glycol 1, 2, 4, 8, 24 h 4-6 35.0 or 10.0 1.0 0.5% MC Oral Single Fasted Pre-dose, 15, 30 min, 1, 2,4, 8, 24 hStudy Design

All procedures performed on animals were in accordance with establishedguidelines and reviewed and approved by an independent institutionalreview board.

The male Sprague-Dawley rats were fasted overnight with free access todrinking water prior to treatment. On day 1, the animals were weighedand actual dose volume for each animal was calculated using the formulabelow:Dose Volume (mL)=[Nominal Dose (mg·kg⁻¹)/Dose Concentration(mg·mL⁻¹)]×Animal Body Weight (kg)   (1)

Three rats were given a single IV dose of 1 mg·kg⁻¹ via tail veininjection and other three rats were given a single oral dose of 5 or 10mg·kg⁻¹. The dosing solutions were freshly prepared prior to doseadministration. The actual body weights and actual volume injected wererecorded accordingly. Four hours after dosing, the rats were allowed tointake food.

Blood samples (˜150 μL) were collected at different times from thejugular vein catheter into EDTA-K₂ coated tubes. Whole Hood wasprocessed by centrifugation at 3000 g for 10 min. Plasma samples werecollected and kept at −80° C. freezer prior to analysis. The bloodsampling time was recorded accordingly.

Sample Test

The dose samples of IV and PO were diluted with MeOH: H₂O (4:1, v/v) toachieve the concentration of 2 μg·mL⁻¹, respectively. Then, 2.5 μL ofthe diluted samples were added with 47.5 μL blank plasma, and then werehandled as the plasma sample procedure. An aliquot of 10 μL of themixture was injected into the LC-MS/MS system. The pharmacokinetic (PK)data of the test compounds were generated as shown in Table 4.

TABLE 4 Rat PK data of Compounds 60 and 73 PO (5 mpk for compound 60 andIV (1 mpk) 10 mpk for compound 73) t_(1/2) Cl AUC_(0-inf) V_(dSS)t_(1/2) t_(max) C_(max) AUC_(0-inf) F % Compound (h) (mL · kg⁻¹ · min⁻¹)(h · ng · mL⁻¹) (L · kg⁻¹) (h) (h) (ng · mL⁻¹) (h · ng · mL⁻¹) 60 0.676.6 218.4 3.3 2.0 0.3 132.8 159.1 14.6 73 8.2 86.6 193.7 59.4 5.6 1.5220.3 918.1 34.9IV. Brain penetration of compounds in male C57BL/6 mice after oraladministrationDose Formulation Preparation

Approximately 4 mg of a test compound was weighed and dispersed in 0.5%methyl cellulose (MC). After that, the whole mixture were vortexed untila solution or suspension was formed. The final concentration of the testcompound was 1 mg·mL⁻¹. The concentration of test compound in dosingformulations was determined within 85% to 115% of nominal values.

Animals

Male C57BL/6 mice were housed in solid bottom polypropylene cages withsterilized bedding. The room was controlled and monitored for humidity(targeted mean range 40% to 70%) and temperature (targeted mean range20° to 25° C.) with 10 to 20 air changes/hour. The room was on a 12-hourlight/dark cycle except when interruptions were necessitated by studyactivities. The mice were supplied with sterilized diet and water. Allanimals were examined upon receipt and were acclimated for at least 3days. Only animals that appeared to be healthy were selected for thestudy based on overall health, body weight, or other relevant data asappropriate.

Study Design

All procedures performed on animals were in accordance with establishedguidelines and reviewed and approved by an independent institutionalreview board. The animals were treated in accordance with a certaintreatment schedule.

The male mice were fasted overnight with free access to drinking waterprior to treatment. On day 1, the animals were weighed and actual dosevolume for each animal was calculated using the formula below:Dose Volume (mL)=[Nominal Dose (mg·kg⁻¹)/Dose Concentration(mg·mL⁻¹)]×Animal Body Weight (kg)   (1)

The mice were administrated with test compound at 10 mg·kg⁻¹ via oralgavage, respectively. The dosing formulations were freshly prepared. Theactual body weights and actual volume administered were recordedaccordingly.

Three mice were sacrificed under carbon dioxide for sample collection at1, 2 and 4 hours post dose, respectively. Blood samples (˜0.2 mL) werecollected via cardiac puncture into anticoagulant tubes (coated withEDTA-Ka). The tubes were gently inverted several times to ensure mixing.Whole blood was processed for plasma by centrifugation at 5,500 rpm for10 min. The brain was collected immediately after euthanasia. The samplecollection time was recorded accordingly, After the removal of excesswater, the brain was weighed and homogenized with 5×water (w/v) in anice bath. The samples were kept below −20° C. freezer prior to analysis.

Sample Test

For plasma samples: An aliquot of 10 μL of sample was added with 500 μLACN which contained IS (Verapamil, 5 ng·mL⁻¹ and Glibenclamide, 50ng·mL⁻¹) for protein precipitation, the mixture was vortexed for 1 min,then centrifuged at 13000 rpm for 8 min, then 70 μL of supernatant wasadded with 70 μL water, then vortexed for 10 min. An aliquot of 10 μL ofthe mixture was injected into the LC-MS/MS system.

For brain samples: An aliquot of 50 μL of sample was added with 250 μLACN which contained IS (Verapamil, 5 ng·mL⁻¹ and Glibenclamide, 50ng·mL⁻¹) for protein precipitation, the mixture was vortexed for 1 min,then centrifuged at 13000 rpm for 8 min, then 70 μL of supernatant wasadded with 70 μL water, then vortexed for 10 min. An aliquot of 10 μL ofthe mixture was injected into the LC-MS/MS system. The blood-brainbarrier (BBB) data of the test compounds were generated.

While the foregoing written description of the invention enables one ofordinary skill to make and use what is considered presently to be thebest mode thereof, those of ordinary skill will understand andappreciate the existence of variations, combinations, and equivalents ofthe specific embodiment, method, and examples herein. The inventionshould therefore not be limited by the above described embodiment,method, and examples, but by all embodiments and methods within thescope and spirit of the invention as claimed.

The invention claimed is:
 1. A compound of Formula (I),

or a stereoisomer thereof, or a pharmaceutically acceptable saltthereof, wherein: R₁ is —NR_(a)R_(b), wherein R_(a) and R_(b) are eachindependently hydrogen or C₁₋₆alkyl; R₂ is hydrogen, F, Cl, Br,—C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, cycloalkyl, heterocyclyl, aryl,heteroaryl, —CN, —NO₂, —OR₁₂, —SO₂R₁₂, —COR₁₂, —CO₂R₁₂, —CONR₁₂R₁₃,—C(═NR₁₂)NR₁₃R₁₄ , —NR₁₂R₁₃, —NR₁₂COR₁₃, —NR₁₂CONR₁₃R₁₄, —NR₁₂CO₂R₁₃,—NR₁₂SONR₁₃R₁₄, —NR₁₂SO₂NR₁₃R₁₄, or —NR₁₂SO₂R₁₃; wherein said—C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, cycloalkyl, heterocyclyl, arylor heteroaryl are each independently optionally substituted with atleast one substituent R_(11a); R₃ and R₄, which may be the same ordifferent, are each independently hydrogen, —C₁₋₆alkyl, cycloalkyl,heterocyclyl, aryl, or heteroaryl; R₅ and R₆, which may be the same ordifferent, are each independently hydrogen, halogen, —C₁₋₆alkyl,—C₂₋₆alkenyl, —C₂₋₆alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl,—CN, —NO₂, —OR₁₂, —SO₂R₁₂, —COR₁₂, —CO₂R₁₂, —CONR₁₂R₁₃,—C(═NR₁₂)NR₁₃R₁₄, —NR₁₂R₁₃, —NR₁₂COR₁₃, —NR₁₂CONR₁₃R₁₄, —NR₁₂CO₂R₁₃,—NR₁₂SONR₁₃R₁₄, —NR₁₂SO₂NR₁₃R₁₄, or —NR₁₂SO₂R₁₃; wherein said—C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, cycloalkyl, heterocyclyl, arylor heteroaryl are each independently optionally substituted with atleast one substituent R_(11b); R₇, R₈ and R₁₀, which may be the same ordifferent, are each independently hydrogen, halogen, —C₁₋₆alkyl,—C₂₋₆alkenyl, —C₂₋₆alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl,—CN, —NO₂, —OR₁₂, —SO₂R₁₂, —COR₁₂, —CO₂R₁₂, —CONR₁₂R₁₃,—C(═NR₁₂)NR₁₃R₁₄, —NR₁₂R₁₃, —NR₁₂COR₁₃, —NR₁₂CONR₁₃R₁₄, —NR₁₂CO₂R₁₃,—NR₁₂SONR₁₃R₁₄, —NR₁₂SO₂NR₁₃R₁₄, or —NR₁₂SO₂R₁₃; wherein said—C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, cycloalkyl, heterocyclyl, arylor heteroaryl are each independently optionally substituted with atleast one substituent R_(11c); R₉ is —CN, —NO₂, —OR₁₂, —SO₂R₁₂,—SO₂NR₁₂R₁₃, —COR₁₂, —CO₂R₁₂, —CONR₁₂R₁₃, —C(═NR₁₂)NR₁₃R₁₄, —NR₁₂COR₁₃,—NR₁₂CONR₁₃R₁₄, —NR₁₂CO₂R₁₃, —NR₁₂SONR₁₃R₁₄, —NR₁₂SO₂NR₁₃R₁₄, or—NR₁₂SO₂R₁₃; R_(11a), R_(11b), and R_(11c), which may be the same ordifferent, are each independently hydrogen, halogen, —C₁₋₆alkyl,—C₂₋₆alkenyl, —C₂₋₆alkynyl, haloC₁₋₆alkyl, haloC₂₋₆alkenyl,haloC₂₋₆alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, —CN, —NO₂,oxo, —OR₁₂, —SO₂R₁₂, —COR₁₂, —CO₂R₁₂, —CONR₁₂R₁₃, —C(═NR₁₂)NR₁₃R₁₄,—NR₁₂R₁₃, —NR₁₂COR₁₃, —NR₁₂CONR₁₃R₁₄, —NR₁₂CO₂R₁₃, —NR₁₂SONR₁₃R₁₄,—NR₁₂SO₂NR₁₃R₁₄, or —NR₁₂SO₂R₁₃; and R₁₂, R₁₃, and R₁₄, which may be thesame or different, are each independently hydrogen, —C₁₋₆alkyl,—C₂₋₆alkenyl, —C₂₋₆alkynyl, cycloalkyl, heterocyclyl, aryl, orheteroaryl, wherein said C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl,cycloalkyl, heterocyclyl, aryl, or heteroaryl are each independentlyoptionally substituted with at least one substituent R₁₅; Alternatively,(R₁₂ and R₁₃), or (R₁₃ and R₁₄), or (R₁₂ and R₁₄), together with theatom(s) to which they are attached, form a 3- to 12-membered saturated,partially or fully unsaturated ring comprising 0, 1 or 2 additionalheteroatoms independently selected from —NH, —O—, —S—, —SO— or —SO₂—,and said ring is optionally substituted with at least one substituentR₁₅; R₁₅, at each of its occurrences, is independently hydrogen,halogen, —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, cycloalkyl,heterocyclyl, aryl, heteroaryl, —CN, —NO₂, oxo, —OR₁₆, —SO₂R₁₆, —COR₁₆,—CO₂R₁₆, —CONR₁₆R₁₇, —C(═NR₁₆)NR₁₇R₁₈, —NR₁₆R₁₇, —C₁₋₆alkyl-NR₁₆R₁₇,—NR₁₆COR₁₇, —NR₁₆CONR₁₇R₁₈, —NR₁₆CO₂R₁₇, —NR₁₆SONR₁₇R₁₈,—NR₁₆SO₂NR₁₇R₁₈, or —NR₁₆SO₂R₁₇, wherein said C₁₋₆alkyl, —C₂₋₆alkenyl,—C₂₋₆alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl are eachindependently optionally substituted with halogen, R₁₉, —OR₁₉, —COR₁₉,—SO₂R₁₉, or —CO₂R₁₉; wherein each of R₁₆, R₁₇, or R₁₈ is independentlyhydrogen, —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, haloC₁₋₆alkyl,haloC₂₋₆alkenyl, haloC₂₋₆alkynyl, cycloalkyl, heterocyclyl, aryl, orheteroaryl; or (R₁₆ and R₁₇), or (R₁₆ and R₁₈), or (R₁₇ and R₁₈),together with the atom(s) to which they are attached, form a 3- to12-membered saturated, partially or fully unsaturated ring comprising 0,1 or 2 additional heteroatoms independently selected from —NH, —O—, —S—,—SO— or —SO₂—, and said ring is optionally substituted with at least onesubstituent R₁₉; and wherein R₁₉ is independently hydrogen, —C₁₋₆alkyl,—C₂₋₆alkenyl, —C₂₋₆alkynyl, haloC₁₋₆alkyl, haloC₂₋₆alkenyl,haloC₂₋₆alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, whereinsaid cycloalkyl, heterocyclyl, aryl, or heteroaryl are each optionallysubstituted with halogen, —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl,haloC₁₋₆alkyl, haloC₂₋₆alkenyl, or haloC₂₋₆alkynyl; and wherein said—C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, haloC₁₋₆alkyl, haloC₂₋₆alkenyl,or haloC₂₋₆alkynyl are each optionally substituted with cycloalkyl,heterocyclyl, aryl, or heteroaryl.
 2. The compound of claim 1, wherein:(a) R₁ is —NH₂; or (b) R₂ is independently hydrogen, halogen,—C₁₋₆alkyl, C₃₋₆cycloalkyl or C₆₋₁₀ aryl, wherein —C₁₋₆alkyl,C₃₋₆cycloalkyl and C₆₋₁₀ aryl are each independently optionallysubstituted with at least one substituent R_(11a); or (c) R₃ and R₄ areeach independently hydrogen or —C₁₋₆alkyl; or (d) R₅ and R₆, which maybe the same or different, are each independently hydrogen, halogen,—C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, cycloalkyl, heterocyclyl, aryl,or heteroaryl, wherein said —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl,cycloalkyl, heterocyclyl, aryl or heteroaryl are each independentlyoptionally substituted with at least one substituent R_(11b), whereinR_(11b) is halogen; or (e) R₇, R₈ and R₁₀, which may be the same ordifferent, are each independently hydrogen, halogen, —C₁₋₆alkyl,—C₂₋₆alkenyl, —C₂₋₆alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl,or —OR₁₂; wherein said —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl,cycloalkyl, heterocyclyl, aryl or heteroaryl are each independentlyoptionally substituted with at least one substituent R_(11c), whereinR_(11c) is halogen.
 3. The compound of claim 2, wherein: (a) R₂ isC₁₋₆alkyl; or (b) R₃ is hydrogen, and R₄ is —C₁₋₆alkyl; or (c) R₅ and R₆are both hydrogen; or (d) R₇ and R₈ are each independently hydrogen,halogen or —C₁₋₆alkyl; or (e) R₁₀ is methoxy, ethoxy, propoxy, orisopropoxy.
 4. The compound of claim 1, wherein R₉ is —CONR₁₂R₁₃.
 5. Thecompound of claim 4, wherein: R₁₂ is hydrogen; R₁₃ is C₁₋₆alklyloptionally substituted with one substituent R₁₅; and R₁₅ is heterocyclyloptionally substituted with halogen, R₁₉, —OR₁₉, —COR₁₉, —SO₂R₁₉, or—CO₂R₁₉.
 6. The compound of claim 5, wherein the heterocyclyl is a 4-,5-, 6-, 7- or 8-membered saturated monocyclic ring comprising onenitrogen heteroatom or a 5-, 6-, 7- or 8-membered saturated monocyclicring comprising one nitrogen atom and 1 additional heteroatom selectedfrom —NH, —O—, —S—, —SO— or —SO₂—, wherein the heterocyclyl isoptionally substituted with halogen, R₁₉, —OR₁₉, —COR₁₉, —SO₂R₁₉, or—CO₂R₁₉.
 7. The compound of claim 6, wherein the heterocyclyl ispiperidinyl or piperazinyl group optionally substituted with halogen orC₁₋₆alkyl.
 8. The compound of claim 4, wherein: R₁₂ is hydrogen; R₁₃ iscycloalkyl optionally substituted with at least one substituent R₁₅; andR₁₅ is —OR₁₆, —CO₂R₁₆ or —C₁₋₆alkyl-NR₁₆R₁₇, or —C₁₋₆alkyl optionallysubstituted with —OR₁₉, wherein R₁₆ and R₁₇ together with the atom(s) towhich they are attached may optionally form a 5- to 8-membered saturatedring comprising 0, 1 or 2 additional heteroatoms independently selectedfrom —NH, and said ring is optionally substituted with at least onesubstituent R₁₉.
 9. The compound of claim 8, wherein R₁₃ is a C₃-C₈cycloalkyl optionally substituted with at least one substituent R₁₅. 10.The compound of claim 9, wherein R₁₃ is a cyclopropyl, cyclobutyl,cyclopentyl, or cyclohexyl, each optionally substituted with at leastone substituent R₁₅ .
 11. The compound of claim 4, wherein: (a) R₁₂ ishydrogen, and R₁₃ is a 5- to 8-membered heterocyclyl comprising 1 or 2or 3 heteroatoms selected from O, NH, S, SO, or SO₂, optionallysubstituted with at least one substituent R₁₅; or (b) R₁₂ is hydrogen,and R₁₃ is an aryl group selected from phenyl and naphthyl, optionallysubstituted with at least one substituent R₁₅; or (c) R₁₂ and R₁₃together with the nitrogen atom to which they are attached, form a 3- to12-membered saturated, partially or fully unsaturated ring comprising 0,1 or 2 additional heteroatoms independently selected from —NH, —O—, —S—,—SO— or —SO₂—, and said ring is optionally substituted with at least onesubstituent R₁₅.
 12. The compound of claim 4, wherein R₁₃ istetrahydrofurfuryl or tetrahydropyranyl, each optionally substitutedwith at least one substituent R₁₅; and wherein R₁₅ is halogen or—C₁₋₆alkyl.
 13. The compound of claim 4, wherein: R₁₂ is hydrogen; R₁₃is an aryl group selected from phenyl and naphthyl, optionallysubstituted with at least one substituent R₁₅; and R₁₅ is halogen,—C₁₋₆alkyl, —OR₁₆, or heterocyclyl optionally substituted with halogen,R₁₉, or —OR₁₉.
 14. The compound of claim 4, wherein R₁₂ and R₁₃ togetherwith the nitrogen atom to which they are attached, form a 4-, or 5- or6- or 7- or 8-membered saturated monocyclic ring comprising 0 additionalheteroatom, and said ring is optionally substituted with at least onesubstituent R₁₅; and wherein R₁₅ is halogen, —OR₁₆, —CO₂R₁₆, or—C₁₋₆alkyl optionally substituted with —OR₁₉.
 15. The compound of claim4, wherein: (a) R₁₂ and R₁₃ together with the nitrogen atom to whichthey are attached, form a 5-, 6-, 7- or 8-membered saturated monocyclicring comprising 1 additional heteroatom selected from —NH, —O—, —S—,—SO— or —SO₂—, and said ring is optionally substituted with at least onesubstituent R₁₅; or (b) R₁₂ and R₁₃ together with the nitrogen atom towhich they are attached, form a 7- to 12-membered saturated bicyclicring comprising 0 or 1 or 2 additional heteroatoms selected from —N,—O—, —S—, —SO— or —SO₂—, and said ring is optionally substituted with atleast one substituent R₁₅.
 16. The compound of claim 15, wherein R₁₂ andR₁₃ together with the nitrogen atom to which they are attached, form amorpholino, morpholinyl or piperazinyl ring, each of which is optionallysubstituted with at least one substituent R₁₅; and wherein R₁₅ ishydrogen, halogen, —C₁₋₆alkyl, or cycloalkyl, wherein said C₁₋₆alkyl, orcycloalkyl are each independently optionally substituted with halogen,R₁₉, —OR₁₉, —COR₁₉, or —CO₂R₁₉.
 17. The compound of claim 15, whereinthe bicyclic ring is


18. The compound of claim 4, wherein R₉ is


19. The compound of claim 1, wherein the carbon atom to which R₃ and R₄are attached is in (S)-configuration when R₃ and R₄ are different. 20.The compound of claim 1 is selected from:

or a stereoisomer thereof, or a pharmaceutically acceptable saltthereof.
 21. The compound of claim 1 selected from:

or a stereoisomer thereof, or a pharmaceutically acceptable saltthereof.
 22. A pharmaceutical composition comprising a therapeuticallyeffective amount of a compound of claim 1, a stereoisomer thereof or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable excipient.